Patent application title: RET INHIBITOR
Inventors:
Tatsushi Kodama (Kanagawa, JP)
Hiroshi Sakamoto (Kanagawa, JP)
Toshiyuki Tsukaguchi (Kanagawa, JP)
Assignees:
Chugai Seiyaku Kabushiki Kaisha
IPC8 Class: AA61K315377FI
USPC Class:
Class name:
Publication date: 2015-10-01
Patent application number: 20150272958
Abstract:
A compound represented by the following general formula (I) [the symbol
in the formula are as defined in the description], a salt thereof, or the
like is a RET inhibitor or RET tyrosine kinase inhibitor that can be used
as an agent for the prevention or treatment of disorders including
cancers and cancer metastasis having mutations in RET.
##STR00001##Claims:
1. A therapeutic and/or prophylactic agent for a tumor with a mutation in
RET and for metastasis of the tumor, which comprises a compound
represented by formula (I), a salt thereof or a solvate thereof as an
active ingredient: ##STR00007## wherein R1 is a C1-6 alkyl
group.
2. The therapeutic and/or prophylactic agent according to claim 1, wherein the tumor is selected from the group consisting of acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, brain tumor, neuroblastoma, glioma, thyroid cancer, myelodysplastic syndrome, head and neck cancer, esophageal cancer, gastric cancer, colorectal cancer, breast cancer, ovarian cancer, lung cancer, pancreatic cancer, liver cancer, gallbladder cancer, skin cancer, malignant melanoma, kidney cancer, renal pelvic and ureteral cancer, bladder cancer, uterine cancer, testicular cancer, prostate cancer, and tumors metastasized from these tumors.
3. The therapeutic and/or prophylactic agent according to claim 1, wherein the tumor is thyroid cancer or lung cancer.
4. The therapeutic and/or prophylactic agent according to claim 1, wherein the tumor is thyroid medullary cancer or non-small cell lung cancer.
5. The therapeutic and/or prophylactic agent according to claim 1, wherein the tumor is a tumor with a fusion gene between RET gene and another gene and/or a fusion protein between RET protein and another protein.
6. The therapeutic and/or prophylactic agent according to claim 1, wherein the tumor is a tumor with a point mutation in RET gene and/or protein.
7. A therapeutic and/or prophylactic agent for a tumor used for a patient with a mutation in RET and for metastasis of the tumor, which comprises a compound represented by formula (I), a salt thereof or a solvate thereof as an active ingredient: ##STR00008## wherein R1 is a C1-6 alkyl group.
8. The therapeutic and/or prophylactic agent according to claim 7, wherein the tumor is thyroid cancer or lung cancer.
9. The therapeutic and/or prophylactic agent according to claim 7, wherein the patient is a patient with a fusion gene between RET gene and another gene and/or a fusion protein between RET protein and another protein.
10. The therapeutic and/or prophylactic agent according to claim 7, wherein the patient is a patient with a point mutation in RET gene and/or protein.
11. The therapeutic and/or prophylactic agent according to claim 1, wherein R1 is ethyl.
12. The therapeutic and/or prophylactic agent according to claim 1, wherein the compound is a hydrochloride.
13. A RET inhibitor, which comprises a compound of formula (I), a salt thereof or a solvate thereof as an active ingredient: ##STR00009## wherein R1 is a C1-6 alkyl group.
14. A method for identifying a patient sensitive to a compound represented by formula (I), a salt thereof or a solvate thereof, which comprises the steps of: detecting the presence of a mutation in RET in a sample obtained from the patient; and determining or preliminarily determining that the patient has sensitivity to the compound, the salt thereof or the solvate thereof, on the basis of the presence of a mutation in RET in the sample: ##STR00010## wherein R1 is a C1-6 alkyl group.
15. The method according to claim 14, wherein the mutation in RET is a mutation which induces activation of RET tyrosine kinase.
16. The method according to claim 14, wherein the mutation in RET is (a) a mutation in the cysteine-rich domain of RET tyrosine kinase, (b) a mutation in the tyrosine kinase domain of RET tyrosine kinase, or (c) the formation of a fusion gene of RET and/or a fusion protein of RET.
17. The method according to claim 14, wherein the tumor is a tumor with a fusion gene of RET and/or a fusion protein of RET.
18. The method according to claim 14, wherein the mutation in RET is (a) a mutation in the cysteine-rich domain of RET tyrosine kinase, (b) a mutation in the tyrosine kinase domain of RET tyrosine kinase, or (c) the formation of a fusion gene between RET gene and another gene and/or a fusion protein between RET protein and another protein.
19. The method according to claim 14, wherein the mutation in RET results in the formation of a fusion gene between RET gene and another gene and/or a fusion protein between RET protein and another protein.
20. The method according to claim 19, wherein the another gene and protein is KIF5B, CCDC6, NCOA4 or TRIM33.
21. The method according to claim 18, wherein the fusion gene between RET gene and another gene and the fusion protein between RET protein and another protein comprise the tyrosine kinase domain of RET gene or protein and the coiled-coil domain of another gene or protein.
22. The method according to claim 14, wherein the mutation in RET is a point mutation.
23. The method according to claim 22, wherein the point mutation is a point mutation in the cysteine-rich domain or in the tyrosine kinase domain of RET tyrosine kinase.
24. The method according to claim 14, wherein the patient is a patient with thyroid cancer or lung cancer.
25. The method according to claim 14, wherein the patient is a patient with thyroid medullary cancer or non-small cell lung cancer.
Description:
TECHNICAL FIELD
[0001] The present invention relates to a RET inhibitor, an inhibitor of RET tyrosine kinase, a prophylactic or therapeutic agent for diseases including cancers with a mutation in RET and their metastasis, a method for identifying a target patient, and the like, each of which comprises a tetracyclic compound or a salt thereof or a solvate thereof.
BACKGROUND ART
[0002] Rearranged during transfection (RET) is a member of the receptor tyrosine kinases belonging to the cadherin superfamily (Surgery, 2007, vol. 141, p. 96-99). RET tyrosine kinase has a transmembrane region in the middle and has a tyrosine kinase region at the carboxyl-terminal side and an extracellular region at the amino-terminal side. It is known that there are three types of proteins due to differences in carboxyl-terminal splicing (TRENDS in Genetics, 2006, vol. 22, p. 627-636: Reference a). RET forms a dimer via a ligand/GFR complex to thereby phosphorylate and activate its own tyrosine (Reference a).
[0003] There are reports showing that RET will be involved in oncogenesis upon alterations (point mutation, chromosomal translocation, chromosomal inversion, gene amplification) in RET gene. For example, in thyroid medullary cancer, it is reported that a point mutation in RET gene results in the expression of RET tyrosine kinase with oncogenic ability (Reference a). Moreover, in thyroid papillary cancer, it is reported that RET gene is fused with another gene (e.g., coiled-coil domain containing 6 (CCDC6) gene or nuclear receptor coactivator 4 (NCOA4) gene) by chromosomal inversion or chromosomal translocation to cause the expression of fused tyrosine kinase RET/PTC with oncogenic ability (European Journal of Endocrinology, 2006, vol. 155, p. 645-653). Further, in non-small cell lung cancer, it is reported that RET is fused with kinesin family protein 5B (KIF5B) gene, which is one of the molecules constituting motor protein complexes involved in intracellular microtubule transport, or with CCDC6 gene to cause non-small cell lung cancer by the constitutive tyrosine kinase activity of fused tyrosine kinase KIF5B-RET or CCDC6-RET with oncogenic ability (Nature Medicine. 2012, 18, p. 378-381, WO2012/014795). Moreover, it is reported that the fused tyrosine kinase NCOA4-RET or TRIM33-RET in which RET gene is fused with NCOA4 gene or TRIM33 (tripartite motif-containing 33) gene is present in non-small cell lung cancer patients (J Clin Oncol, 30 (35), Dec. 10, 2012, p. 4352-9; and Cancer Discov 2013 June, 3 (6). June 2013, p. 630-5).
[0004] In view of the foregoing, compounds having an inhibitory effect against RET tyrosinc kinase are very useful for cancer prevention and treatment.
[0005] As inhibitory substances of RET tyrosine kinase, multi-kinase inhibitors such as sorafenib, sunitinib, XL184, vandetanib and ponatinib are reported to have a cell growth inhibitory effect against cell lines expressing KIF5B-RET (Non-patent Document 1: J Clin Oncol 30, 2012, suppl; Abstract no: 7510). Moreover, it is reported that two patients who have RET fusion gene-positive non-small cell lung cancer exhibited partial response to the multi-kinase inhibitor cabozantinib (Non-Patent Document 2: Cancer Discov, 3 (6). June 2013, p. 630-5).
[0006] On the other hand, a tetracyclic compound having the following general formula is reported as an inhibitor of anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase belonging to the insulin receptor family (Patent Document 1: WO2010/143664, Patent Document 2: WO2012/023597, Patent Document 3: Japanese Patent Laid-Open No. 2012-126711). This compound is useful as a therapeutic and/or prophylactic agent for tumors with a mutation in ALK gene.
##STR00002##
(see the above patent gazette for details of substituents, etc.)
[0007] Moreover, it is reported that the following compound with a high concentration (1,000 nM) inhibits many kinases including RET in the Ambit Kinase Screening test (Non-Patent Document 3: Cancer Cell, 19 (5), p. 679-690, 2011, Supplemental Information):
##STR00003##
[0008] However, there is no report showing that the tetracyclic compound found in Patent Document 1 and Non-patent Document 3 is useful as a therapeutic or prophylactic agent for cancers with a mutation in RET.
[0009] Moreover, it is reported that the ALK inhibitor crizotinib has no cell growth inhibitory activity against KIF51B-RET-expressing cells (Non-Patent Document 4: Nature Medicine. 2012, 18, p. 378-381).
DOCUMENT LIST
Patent Document
[0010] [Patent Document 1] WO2010/143664
[0011] [Patent Document 2] WO2012/023597
[0012] [Patent Document 3] JP2012-126711A
Non-Patent Document
[0012]
[0013] [Non-Patent Document 1] J Clin Oncol 30, 2012, suppl; Abstract no: 7510
[0014] [Non-Patent Document 2] Cancer Discov, 3 (6), June 2013, p. 630-5
[0015] [Non-Patent Document 3] Cancer Cell, 19 (5), p. 679-690, 2011, Supplemental Information
[0016] [Non-Patent Document 4] Nature Medicine. 2012, 18, p. 378-381
SUMMARY OF THE INVENTION
Problem to be Solved by the Invention
[0017] Cancers caused by a mutation in ALK gene and cancers caused by a mutation in RET gene differ in their mechanism of cancer development, the three-dimensional protein structure of their respective kinases, etc., and hence a specific therapeutic and/or prophylactic method is required for each cancer. In lung cancer, it is reported that a group of patients with a mutation in ALK gene does not overlap with a group of patients with a mutation in RET (Nat Med, 2012 Feb. 12, 18 (3), 375-7). These patient groups are clearly distinguished from each other for treatment, and the patients in each group require a specific treatment and/or prevention method.
[0018] On the other hand, a compound which inhibits multiple kinases at the same time is known to show a lower therapeutic effect in some cases, because its effective therapeutic range is narrow. Thus, a drug which selectively inhibits a small number of kinases can be regarded as having desired properties in terms of therapeutic effect, and hence there is a demand for such a drug.
Means to Solve the Problem
[0019] As a result of extensive and intensive efforts made to solve the above problem, the inventors of the present invention have found, ahead of others, that a tetracyclic compound represented by the following formula (I) or a salt thereof or a solvate thereof has not only inhibitory activity against ALK but also potent inhibitory activity against RET, selectively inhibits RET, is useful for treatment and prevention of diseases including cancers with a mutation in RET and their metastasis, and also has high therapeutic efficacy on these diseases. This finding led to the completion of the present invention.
##STR00004##
wherein R1 is a C1-6 alkyl group.
[0020] Namely, according to one aspect of the present invention, the present invention is directed to a therapeutic or prophylactic agent for cancers with a mutation in RET and their metastasis, which comprises a tetracyclic compound shown blow or a salt thereof, etc. According to another aspect, the present invention provides a method for identifying a cancer or a target patient responsive to treatment with the above compound or the like.
[0021] More specifically, the present invention is as follows.
[1]A therapeutic and/or prophylactic agent for a tumor with a mutation in RET or for metastasis of the tumor, which comprises a compound represented by formula (I), a salt thereof or a solvate thereof as an active ingredient:
##STR00005##
wherein R1 is a C1-6 alkyl group. [2] The therapeutic and/or prophylactic agent according to [1] above, wherein the tumor is selected from the group consisting of acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, brain tumor, neuroblastoma, glioma, thyroid cancer, myelodysplastic syndrome, head and neck cancer, esophageal cancer, gastric cancer, colorectal cancer, breast cancer, ovarian cancer, lung cancer, pancreatic cancer, liver cancer, gallbladder cancer, skin cancer, malignant melanoma, kidney cancer, renal pelvic and ureteral cancer, bladder cancer, uterine cancer, testicular cancer, prostate cancer, and tumors metastasized from these tumors. [3] The therapeutic and/or prophylactic agent according to [1] or [2] above, wherein the tumor is thyroid cancer or lung cancer. [4] The therapeutic and/or prophylactic agent according to any one of [1] to [3] above, wherein the tumor is thyroid medullary cancer or non-small cell lung cancer. [4-1] The therapeutic and/or prophylactic agent according to [1] to [4] above, wherein the tumor is a tumor confirmed to show activated RET tyrosine kinase in the tumor tissue. [4-2] The therapeutic and/or prophylactic agent according to [1] to [4] above, wherein the tumor is a tumor with a mutation which induces activation of RET tyrosine kinase. [4-2-1] The therapeutic and/or prophylactic agent according to any one of [1] to [4-2] above, wherein the tumor is a tumor with (a) a mutation in the cysteine-rich domain of RET tyrosine kinase, (b) a mutation in the tyrosine kinase domain of RET tyrosine kinase, or (c) a fusion gene of RET and/or a fusion protein of RET. [4-2-2] The therapeutic and/or prophylactic agent according to any one of [1] to [4-2] above, wherein the tumor is a tumor with a fusion gene of RET and/or a fusion protein of RET. [4-2-3] The therapeutic and/or prophylactic agent according to any one of [1] to [4-2] and [4-2-2] above, wherein the tumor is a tumor with KIF5B-RET, CCDC6-RET, NCOA4-RET or TRIM33-RET. [4-3] The therapeutic and/or prophylactic agent according to [1] to [4-2] above, wherein the tumor is a tumor with (a) a mutation in the cysteine-rich domain of RET tyrosine kinase, (b) a mutation in the tyrosine kinase domain of RET tyrosine kinase, or (c) a fusion gene between RET gene and another gene and/or a fusion protein between RET protein and another protein. [5] The therapeutic and/or prophylactic agent according to any one of [1] to [4-2] above, wherein the tumor is a tumor with a fusion gene between RET gene and another gene and/or a fusion protein between RET protein and another protein. [5-1] The therapeutic and/or prophylactic agent according to [5] above, wherein the another gene and protein are the gene and protein of KIF5B, CCDC6 or NCOA4 or TRIM33. [5-2] The therapeutic and/or prophylactic agent according to [5] or [5-1] above, wherein the fusion gene and protein comprises the tyrosine kinase domain of RET gene or protein and the coiled-coil domain of another gene or protein. [5-2-1] The therapeutic and/or prophylactic agent according to any one of [5] to [5-2] above, wherein a polypeptide constituting the RET protein and a polynucleotide constituting the RET gene are any of the following polypeptides and any of polynucleotides encoding the polypeptides: (a) a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 3 or 4; (b) a polypeptide consisting of an amino acid sequence with substitution, deletion or insertion of one or more amino acids in the polypeptide shown in SEQ ID NO: 3 or 4; and (c) a polypeptide consisting of an amino acid sequence with 80% or higher identity to the amino acid sequence shown in SEQ ID NO: 3 or 4. [5-2-2] The therapeutic and/or prophylactic agent according to [5-1] or [5-2-1] above, wherein a polypeptide constituting each of the KIF5B, CCDC6, NCOA4 and TRIM33 proteins and a polynucleotide constituting each of the KIF5B, CCDC6. NCOA4 and TRIM33 genes are any of the following polypeptides and any of polynucleotides encoding the polypeptides: (1) the polypeptide constituting the KIF5B protein is (a) a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 30, (b) a polypeptide consisting of an amino acid sequence with substitution, deletion or insertion of one or more amino acids in the amino acid sequence shown in SEQ ID NO: 30, or (c) a polypeptide consisting of an amino acid sequence with 80% or higher identity to the amino acid sequence shown in SEQ ID NO: 30; (2) the polypeptide constituting the CCDC6 protein is (a) a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 31, (b) a polypeptide consisting of an amino acid sequence with substitution, deletion or insertion of one or more amino acids in the amino acid sequence shown in SEQ ID NO: 31, or (c) a polypeptide consisting of an amino acid sequence with 80% or higher identity to the amino acid sequence shown in SEQ ID NO: 31; (3) the polypeptide constituting the NCOA4 protein is (a) a polypeptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 38 to 42, (b) a polypeptide consisting of an amino acid sequence with substitution, deletion or insertion of one or more amino acids in an amino acid sequence selected from the group consisting of SEQ ID NOs: 38 to 42, or (c) a polypeptide consisting of an amino acid sequence with 80% or higher identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 38 to 42; and (4) the polypeptide constituting the TRIM33 protein is (a) a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 45 or 46, (b) a polypeptide consisting of an amino acid sequence with substitution, deletion or insertion of one or more amino acids in the amino acid sequence shown in SEQ ID NO: 45 or 46, or (c) a polypeptide consisting of amino acid sequence with 80% or higher identity to the amino acid sequence shown in SEQ ID NO: 45 or 46. [5-2-3] The therapeutic and/or prophylactic agent according to [4-2-2], [5] or [5-2] above, wherein a polypeptide constituting the fusion protein and a polynucleotide constituting the fusion gene are any of the following polypeptides (a) to (f) and any of polynucleotides encoding the polypeptides: (a) a polypeptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24; (b) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24, or a polypeptide comprising an amino acid sequence with substitution, deletion or insertion of one or more amino acids in an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24; (c) a polypeptide comprising an amino acid sequence with 80% or higher identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24; (d) a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 27 or 28; (e) a polypeptide comprising the amino acid sequence shown in SEQ ID NO: 27 or 28, or a polypeptide comprising an amino acid sequence with substitution, deletion or insertion of one or more amino acids in the amino acid sequence shown in SEQ ID NO: 27 or 28; and (f) a polypeptide comprising an amino acid sequence with 80% or higher identity to the amino acid sequence shown in SEQ ID NO: 27 or 28. [5-2-4] The therapeutic and/or prophylactic agent according to [4-2-2], [5] or [5-2] above, wherein a polypeptide constituting the fusion protein and a polynucleotide constituting the fusion gene are any of the following polypeptides (a) to (f) and any of polynucleotides encoding the polypeptides: (a) a polypeptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24; (b) a polypeptide which comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24 and which carriers activated tyrosine kinase, or a polypeptide which comprises an amino acid sequence with substitution, deletion or insertion of 1 to 10 amino acids in an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24 and which has tyrosine kinase activity; (c) a polypeptide which comprises an amino acid sequence with 90% or higher identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24 and which has tyrosine kinase activity; (d) a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 27 or 28; (e) a polypeptide which comprises the amino acid sequence shown in SEQ ID NO: 27 or 28 and which carries activated RET tyrosine kinase, or a polypeptide which comprises an amino acid sequence with substitution, deletion or insertion of 1 to 10 amino acids in the amino acid sequence shown in SEQ ID NO: 27 or 28 and which has tyrosine kinase activity; and (f) a polypeptide which comprises an amino acid sequence with 90% or higher identity to the amino acid sequence shown in SEQ ID NO: 27 or 28 and which has tyrosine kinase activity. [5-3] The therapeutic and/or prophylactic agent according to [5-2] above, wherein the fusion gene is any of (a) to (d) shown below: (a) a fusion gene which comprises a polynucleotide having a nucleotide sequence selected from the group consisting of SEQ ID NOs: 5 to 14; (b) a fusion gene consisting of a polynucleotide which hybridizes under stringent conditions to DNA consisting of a nucleotide sequence complementary to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 5 to 14 and which encodes a polypeptide having tyrosine kinase activity; (c) a fusion gene which comprises a polynucleotide encoding a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24; or (d) a fusion gene comprising a polynucleotide encoding a polypeptide which has substitution, deletion or insertion of one or more (e.g., several tens, 1 to 10, 1 to 5, 1 to 3) amino acids in a polypeptide having an amino acids sequence selected from the group consisting of SEQ ID NOs: 15 to 24 and which has tyrosine kinase activity. [6] The therapeutic and/or prophylactic agent according to any one of [1] to [4-2] above, wherein the tumor is a tumor with a point mutation in RET gene and/or protein. [6-1] The therapeutic and/or prophylactic agent according to [6] above, wherein the point mutation is a mutation in the nucleotide 2091G, 2261G, 2494G, 2562A, 2600G, 2861T or 2943T of a polynucleotide having the nucleotide sequence shown in SEQ ID NO: 1. [6-1-1] The therapeutic and/or prophylactic agent according to [6] or [6-1] above, wherein the point mutation is a mutation in the nucleotide 2091G, 2261 G, 2494G, 2562A or 2861T of a polynucleotide having the nucleotide sequence shown in SEQ ID NO: 1. [6-2] The therapeutic and/or prophylactic agent according to [6] or [6-1] above, wherein the point mutation is a mutation in the nucleotide 2091 G, 2494G, 2600G or 2943T of a polynucleotide having the nucleotide sequence shown in SEQ ID NO: 1. [6-3] The therapeutic and/or prophylactic agent according to [6] or [6-1] above, wherein the point mutation is 2091G>T, 2261G>A, 2494G>C, 2562A>T, 2600G>A, 2600G>C, 2861T>G or 2943T>C in a polynucleotide having the nucleotide sequence shown in SEQ ID NO: 1. [6-3-1] The therapeutic and/or prophylactic agent according to [6], [6-1] or [6-3] above, wherein the point mutation is 2091G>T, 2261G>A, 2494G>C, 2562A>T or 2861T>G in a polynucleotide having the nucleotide sequence shown in SEQ ID NO: 1. [6-4] The therapeutic and/or prophylactic agent according to [6], [6-1], [6-2] or [6-3] above, wherein the point mutation is 2091G>T, 2494G>C, 2600G>A or 2943T>C in a polynucleotide having the nucleotide sequence shown in SEQ ID NO: 1. [6-5] The therapeutic and/or prophylactic agent according to [6] above, wherein the point mutation is a mutation in the amino acid C609, C611, C618, C620, C630, C634, G691, E768, Y791, V804, S891, A883 or M918 of a polypeptide having the amino acid sequence shown in SEQ ID NO: 3. [6-5-1] The therapeutic and/or prophylactic agent according to [6] or [6-5] above, wherein the point mutation is a mutation in the amino acid C609, C611, C618, C620, C630, C634, G691, E768, Y791, 5891 or A883 of a polypeptide having the amino acid sequence shown in SEQ ID NO: 3. [6-6] The therapeutic and/or prophylactic agent according to [6] or [6-5] above, wherein the point mutation is a mutation in the amino acid C609, C611, C618, C620, C630, C634, E768, V804, S891, A883 or M918 of a polypeptide having the amino acid sequence shown in SEQ ID NO: 3. [6-7] The therapeutic and/or prophylactic agent according to [6] or [6-5] above, wherein the point mutation is C634W, C634Y, G691S, E768D, Y791F, V804M, V804L. S891A or M918T in a polypeptide having the amino acid sequence shown in SEQ ID NO: 3. [6-7-1] The therapeutic and/or prophylactic agent according to [6], [6-5] or [6-7] above, wherein the point mutation is C634W, C634Y, G691S, E768D, Y791F or S891A in a polypeptide having the amino acid sequence shown in SEQ ID NO: 3. [6-8] The therapeutic and/or prophylactic agent according to [6] or [6-6] above, wherein the point mutation is C634W, C634Y, E768D, V804M or M918T in a polypeptide having the amino acid sequence shown in SEQ ID NO: 3. [7]A therapeutic and/or prophylactic agent for a tumor used for a patient with a mutation in RET or for metastasis of the tumor, which comprises a compound represented by formula (I), a salt thereof or a solvate thereof as an active ingredient. [8] The therapeutic and/or prophylactic agent according to [7] above, wherein the tumor is thyroid cancer or lung cancer. [8-1] The therapeutic and/or prophylactic agent according to [7] or [8] above, wherein the patient is a patient confirmed to show activated RET tyrosine kinase in the tumor tissue. [8-2] The therapeutic and/or prophylactic agent according to [7] or [8] above, wherein the patient is a patient with a mutation which induces activation of RET tyrosine kinase. [8-2-1] The therapeutic and/or prophylactic agent according to any one of [7] to [8-2] above, wherein the patient is a patient with (a) a mutation in the cysteine-rich domain of RET tyrosine kinase, (b) a mutation in the tyrosine kinase domain of RET tyrosine kinase, or (c) a fusion gene of RET and/or a fusion protein of RET. [8-2-2] The therapeutic and/or prophylactic agent according to any one of [7] to [8-2-1] above, wherein the patient is a patient with a fusion gene of RET and/or a fusion protein of RET. [8-2-3] The therapeutic and/or prophylactic agent according to any one of [7] to [8-2] and [8-2-2] above, wherein the patient is a patient with KIF5B-RET, CCDC6-RET, NCOA4-RET or TRIM33-RET. [8-3] The therapeutic and/or prophylactic agent according to any one of [7] to [8-2] above, wherein the patient is a patient with (a) a mutation in the cysteine-rich domain of RET tyrosine kinase, (b) a mutation in the tyrosine kinase domain of RET tyrosine kinase, or (c) a fusion gene between RET gene and another gene and/or a fusion protein between RET protein and another protein.
[9] The therapeutic and/or prophylactic agent according to [7] or [8] above, wherein the patient is a patient with a fusion gene between RET gene and another gene and/or a fusion protein between RET protein and another protein. [9-1] The therapeutic and/or prophylactic agent according to [8-3] or [9] above, wherein the another gene and protein are KIF5B, CCDC6, NCOA4 or TRIM33. [9-2] The therapeutic and/or prophylactic agent according to [9] or [9-1] above, wherein the fusion gene and fusion protein comprises the tyrosine kinase domain of RET gene or protein and the coiled-coil domain of another gene or protein. [9-2-1] The therapeutic and/or prophylactic agent according to any one of [9] to [9-2] above, wherein a polypeptide constituting the RET protein and a polynucleotide constituting the RET gene are any of the following polypeptides and any of polynucleotides encoding the polypeptides: (a) a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 3 or 4; (b) a polypeptide consisting of an amino acid sequence with substitution, deletion or insertion of one or more amino acids in the polypeptide shown in SEQ ID NO: 3 or 4: and (c) a polypeptide consisting of an amino acid sequence with 80% or higher identity to the amino acid sequence shown in SEQ ID NO: 3 or 4. [9-2-2] The therapeutic and/or prophylactic agent according to [9-1] above, wherein a polypeptide constituting each of the KIF5B, CCDC6, NCOA4 and TRIM33 proteins and a polynucleotide constituting each of the KIF5B, CCDC6, NCOA4 and TRIM33 genes are any of the following polypeptides and any of polynucleotides encoding the polypeptides: (1) the polypeptide constituting the KIF5B protein is (a) a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 30, (b) a polypeptide consisting of an amino acid sequence with substitution, deletion or insertion of one or more amino acids in the amino acid sequence shown in SEQ ID NO: 30, or (c) a polypeptide consisting of an amino acid sequence with 80% or higher identity to the amino acid sequence shown in SEQ ID NO: 30; (2) the polypeptide constituting the CCDC6 protein is (a) a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 31, (b) a polypeptide consisting of an amino acid sequence with substitution, deletion or insertion of one or more amino acids in the amino acid sequence shown in SEQ ID NO: 31, or (c) a polypeptide consisting of an amino acid sequence with 80% or higher identity to the amino acid sequence shown in SEQ ID NO: 31; (3) the polypeptide constituting the NCOA4 protein is (a) a polypeptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 38 to 42, (b) a polypeptide consisting of an amino acid sequence with substitution, deletion or insertion of one or more amino acids in an amino acid sequence selected from the group consisting of SEQ ID NOs: 38 to 42, or (c) a polypeptide consisting of an amino acid sequence with 80% or higher identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 38 to 42; and (4) the polypeptide constituting the TRIM33 protein is (a) a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 45 or 46, (b) a polypeptide consisting of an amino acid sequence with substitution, deletion or insertion of one or more amino acids in the amino acid sequence shown in SEQ ID NO: 45 or 46, or (c) a polypeptide consisting of an amino acid sequence with 80% or higher identity to the amino acid sequence shown in SEQ ID NO: 45 or 46. [9-2-3] The therapeutic and/or prophylactic agent according to [8-2-2] or [9] above, wherein a polypeptide constituting the fusion protein and a polynucleotide constituting the fusion gene are any of the following polypeptides (a) to (f) and any of polynucleotides encoding the polypeptides: (a) a polypeptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24; (b) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24, or a polypeptide comprising an amino acid sequence with substitution, deletion or insertion of one or more amino acids in an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24; (c) a polypeptide comprising an amino acid sequence with 80% or higher identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24; (d) a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 27 or 28: (e) a polypeptide comprising the amino acid sequence shown in SEQ ID NO: 27 or 28, or a polypeptide comprising an amino acid sequence with substitution, deletion or insertion of one or more amino acids in the amino acid sequence shown in SEQ ID NO: 27 or 28; and (f) a polypeptide comprising an amino acid sequence with 80% or higher identity to the amino acid sequence shown in SEQ ID NO: 27 or 28. [9-2-4] The therapeutic and/or prophylactic agent according to [8-2-2] or [9] above, wherein a polypeptide constituting the fusion protein and a polynucleotide constituting the fusion gene are any of the following polypeptides (a) to (f) and any of polynucleotides encoding the polypeptides: (a) a polypeptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24; (b) a polypeptide which comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24 and which carriers activated tyrosine kinase, or a polypeptide which comprises an amino acid sequence with substitution, deletion or insertion of 1 to 10 amino acids in an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24 and which has tyrosine kinase activity; (c) a polypeptide which comprises an amino acid sequence with 90% or higher identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24 and which has tyrosine kinase activity; (d) a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 27 or 28; (e) a polypeptide which comprises the amino acid sequence shown in SEQ ID NO: 27 or 28 and which carries activated RET tyrosine kinase, or a polypeptide which comprises an amino acid sequence with substitution, deletion or insertion of 1 to 10 amino acids in the amino acid sequence shown in SEQ ID NO: 27 or 28 and which has tyrosine kinase activity; and (f) a polypeptide which comprises an amino acid sequence with 90% or higher identity to the amino acid sequence shown in SEQ ID NO: 27 or 28 and which has tyrosine kinase activity. [9-3] The therapeutic and/or prophylactic agent according to [9] or [9-2] above, wherein the fusion gene is any of (a) to (d) shown below: (a) a fusion gene which comprises a polynucleotide having a nucleotide sequence selected from the group consisting of SEQ ID NOs: 5 to 14; (b) a fusion gene consisting of a polynucleotide which hybridizes under stringent conditions to DNA consisting of a nucleotide sequence complementary to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 5 to 14 and which encodes a polypeptide having tyrosine kinase activity; (c) a fusion gene which comprises a polynucleotide encoding a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24; or (d) a fusion gene comprising a polynucleotide encoding a polypeptide which has substitution, deletion or insertion of one or more (e.g., several tens, 1 to 10, 1 to 5, 1 to 3) amino acids in a polypeptide having an amino acids sequence selected from the group consisting of SEQ ID NOs: 15 to 24 and which has tyrosine kinase activity. [10] The therapeutic and/or prophylactic agent according to [7] or [8] above, wherein the patient is a patient with a point mutation in RET gene and/or protein. [10-1] The therapeutic and/or prophylactic agent according to [10] above, wherein the point mutation in RET is a point mutation in the cysteine-rich domain or in the tyrosine kinase domain of RET tyrosine kinase. [10-2] The therapeutic and/or prophylactic agent according to [10] or [10-1] above, wherein the point mutation is a mutation in the nucleotide 2091G, 2261G, 2494G, 2562A, 26000, 28611T or 2943T of a polynucleotide having the nucleotide sequence shown in SEQ ID NO: 1. [10-2-1] The therapeutic and/or prophylactic agent according to any one of [10] to [10-2] above, wherein the point mutation is a mutation in the nucleotide 2091 G, 2261G, 24946, 2562A or 2861 T of a polynucleotide having the nucleotide sequence shown in SEQ ID NO: 1. [10-3] The therapeutic and/or prophylactic agent according to any one of [10] to [10-2], wherein the point mutation in RET is a mutation in the nucleotide 2091G, 2494G, 2600G or 2943T of a polynucleotide having the nucleotide sequence shown in SEQ ID NO: 1. [10-4] The therapeutic and/or prophylactic agent according to any one of [10] to [10-2] above, wherein the point mutation is 2091G>T, 2261G>A, 2494G>C, 2562A>T, 2600G>A, 2600G>C, 2861T>G or 2943T>C in a polynucleotide having the nucleotide sequence shown in SEQ ID NO: 1. [10-4-1] The therapeutic and/or prophylactic agent according to any one of [10] to [10-2] and [10-4] above, wherein the point mutation is 2091G>T, 2261G>A, 2494G>C, 2562A>T or 2861T>G in a polynucleotide having the nucleotide sequence shown in SEQ ID NO: 1. [10-5] The therapeutic and/or prophylactic agent according to any one of [10] to [10-2], [10-4] above, wherein the point mutation in RET is 2091G>T, 2494G>C, 2600G>A or 2943T>C in a polynucleotide having the nucleotide sequence shown in SEQ ID NO: 1. [10-6] The therapeutic and/or prophylactic agent according to [10] or [10-1] above, wherein the point mutation is a mutation in the amino acid C609, C611, C618, C620, C630, C634, G691, E768, Y791, V804, S891. A883 or M918 of a polypeptide having the amino acid sequence shown in SEQ ID NO: 3. [10-6-1] The therapeutic and/or prophylactic agent according to [10], [10-1] or [10-6] above, wherein the point mutation is a mutation in the amino acid C609, C611, C618, C620, C630, C634, G691, E768, Y791, S891 or A883 of a polypeptide having the amino acid sequence shown in SEQ ID NO: 3. [10-7] The therapeutic and/or prophylactic agent according to [10], [10-1] or [10-6] above, wherein the point mutation in RET is a mutation in the amino acid C609, C611, C618, C620, C630, C634, E768, V804, S891, A883 or M918 of a polypeptide having the amino acid sequence shown in SEQ ID NO: 3. [10-8] The therapeutic and/or prophylactic agent according to [10], [10-1] or [10-6] above, wherein the point mutation is C634W, C634Y, G691S. E768D, Y791F, V804M, V804L, S891A or M918T in a polypeptide having the amino acid sequence shown in SEQ ID NO: 3. [10-8-1] The therapeutic and/or prophylactic agent according to [10], [10-1], [10-6] or [10-8] above, wherein the point mutation is C634W, C634Y, G691S, E768D, Y791F or S891A in a polypeptide having the amino acid sequence shown in SEQ ID NO: 3. [10-9] The therapeutic and/or prophylactic agent according to any one of [10], [10-1] or [10-6] to [10-8] above, wherein the point mutation in RET is C634Y, E768D, V804M or M918T in a polypeptide having the amino acid sequence shown in SEQ ID NO: 3. [10-10] The therapeutic and/or prophylactic agent according to any one of [10] to [10-9] above, wherein the patient is a patient detected for the presence of a mutation in RET by Sanger sequencing or FISH method. [11] The therapeutic and/or prophylactic agent according to any one of [1] to [10-10] above, wherein R1 is ethyl. [11-1] The therapeutic and/or prophylactic agent according to any one of [1] to [11] above, wherein the compound is a hydrochloride. [11-2] The therapeutic and/or prophylactic agent according to any one of [1] to [11-S] above, wherein the therapeutic and/or prophylactic agent selectively inhibits RET. [12]A RET inhibitor, which comprises a compound of formula (I), a salt thereof or a solvate thereof as an active ingredient. [12-1] Use of a compound of formula (I), a salt thereof or a solvate thereof for inhibition of RET. [12-2]A method for preventing and/or treating a tumor with a mutation in RET and metastasis of the tumor, which comprises administering a patient with an effective therapeutic amount of a compound represented by formula (I), a salt thereof or a solvate thereof. [12-3] Use of a compound represented by formula (I), a salt thereof or a solvate thereof for prevention and/or treatment of a tumor with a mutation in RET and metastasis of the tumor. [12-3-1] The use according to [12-3] above, wherein the mutation in RET is (a) a mutation in the cysteine-rich domain of RET tyrosine kinase, (b) a mutation in the tyrosine kinase domain of RET tyrosine kinase, or (c) the formation of a fusion gene of RET and/or a fusion protein of RET. [12-3-2] The use according to [12-3] or [12-3-1] above, wherein the mutation in RET results in the formation of a fusion gene of RET and/or a fusion protein of RET. [12-3-3] The use according to any one of [12] to [12-2-2] above, wherein the mutation in RET results in the formation of KIF5B-RET, CCDC6-RET, NCOA4-RET or TRIM33-RET. [12-3-4] The use according to any one of [12-3] to [12-3-3] above, wherein the compound of formula (I), the salt thereof or the solvate thereof selectively inhibits RET. [12-3-5] The use according to any one of [12-3] to [12-3-4] above, wherein R1 is ethyl. [12-3-6] The use according to any one of [12-3] to [112-3-5] above, wherein the compound is a hydrochloride. [12-3-7] The use according to any one of [12-3] to [12-3-6] above, wherein the tumor is thyroid cancer or lung cancer. [13]A method for identifying a subject to be administered with a compound represented by formula (I), a salt thereof or a solvate thereof, which comprises the step of detecting a mutation in RET in a tissue from the subject. [13-1] The method according to [13] above, wherein the tissue is a tissue confirmed to show activated RET tyrosine kinase. [13-2] The method according to [13] above, wherein the tissue has a mutation which induces activation of RET tyrosine kinase. [13-2-1] The method according to any one of [13] to [13-2] above, wherein the mutation in RET is (a) a mutation in the cysteine-rich domain of RET tyrosine kinase, (b) a mutation in the tyrosine kinase domain of RET tyrosine kinase, or (c) the formation of a fusion gene of RET and/or a fusion protein of RET. [13-2-2] The method according to any one of [13] to [13-2-1] above, wherein the mutation in RET results in the formation of a fusion gene of RET and/or a fusion protein of RET. [13-2-3] The method according to any one of [13] to [13-2-2] above, wherein the mutation in RET results in the formation of KIF5B-RET, CCDC6-RET, NCOA4-RET or TRIM33-RET. [13-3] The method according to any one of [13] to [13-2] above, wherein the tissue has (a) a mutation in the cysteine-rich domain of RET tyrosine kinase, (b) a mutation in the tyrosine kinase domain of RET tyrosine kinase, or (c) a fusion gene between RET gene and another gene and/or a fusion protein between RET protein and another protein.
[13-4] The method according to any one of [13] to [13-3] above, wherein the mutation in RET results in the formation of a fusion gene between RET gene and another gene and/or a fusion protein between RET protein and another protein. [13-5] The method according to [13-4] above, wherein another gene and protein are KIF5B, CCDC6, NCOA4 or TRIM33. [13-6] The method according to [13-5] above, wherein the fusion gene and fusion protein comprise the tyrosine kinase domain of RET gene or protein and the coiled-coil domain of another gene or protein. [13-6-1] The method according to any one of [13-4] to [13-6] above, wherein a polypeptide constituting the RET protein and a polynucleotide constituting the RET gene are any of the following polypeptides and any of polynucleotides encoding the polypeptides: (a) a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 3 or 4; (b) a polypeptide consisting of an amino acid sequence with substitution, deletion or insertion of one or more amino acids in the polypeptide shown in SEQ ID NO: 3 or 4; and (c) a polypeptide consisting of an amino acid sequence with 80% or higher identity to the amino acid sequence shown in SEQ ID NO: 3 or 4. [13-6-2] The method according to [13-5] above, wherein a polypeptide constituting each of the KIF5B, CCDC6, NCOA4 and TRIM33 proteins and a polynucleotide constituting each of the KIF5B, CCDC6, NCOA4 and TRIM33 genes are any of the following polypeptides and any of polynucleotides encoding the polypeptides: (1) the polypeptide constituting the KIF5B protein is (a) a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 30, (b) a polypeptide consisting of an amino acid sequence with substitution, deletion or insertion of one or more amino acids in the amino acid sequence shown in SEQ ID NO: 30, or (c) a polypeptide consisting of an amino acid sequence with 80% or higher identity to the amino acid sequence shown in SEQ ID NO: 30; (2) the polypeptide constituting the CCDC6 protein is (a) a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 31, (b) a polypeptide consisting of an amino acid sequence with substitution, deletion or insertion of one or more amino acids in the amino acid sequence shown in SEQ ID NO: 31, or (c) a polypeptide consisting of an amino acid sequence with 80% or higher identity to the amino acid sequence shown in SEQ ID NO: 31; (3) the polypeptide constituting the NCOA4 protein is (a) a polypeptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 38 to 42, (b) a polypeptide consisting of an amino acid sequence with substitution, deletion or insertion of one or more amino acids in an amino acid sequence selected from the group consisting of SEQ ID NOs: 38 to 42, or (c) a polypeptide consisting of an amino acid sequence with 80% or higher identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 38 to 42; and (4) the polypeptide constituting the TRIM33 protein is (a) a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 45 or 46, (b) a polypeptide consisting of an amino acid sequence with substitution, deletion or insertion of one or more amino acids in the amino acid sequence shown in SEQ ID NO: 45 or 46, or (c) a polypeptide consisting of an amino acid sequence with 80% or higher identity to the amino acid sequence shown in SEQ ID NO: 45 or 46. [13-6-3] The method according to [13-2-1], [13-2-2], [13-3] or [13-4] above, wherein a polypeptide constituting the fusion protein and a polynucleotide constituting the fusion gene are any of the following polypeptides (a) to (f) and any of polynucleotides encoding the polypeptides: (a) a polypeptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24; (b) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24, or a polypeptide comprising an amino acid sequence with substitution, deletion or insertion of one or more amino acids in an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24; (c) a polypeptide comprising an amino acid sequence with 80% or higher identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24; (d) a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 27 or 28; (e) a polypeptide comprising the amino acid sequence shown in SEQ ID NO: 27 or 28, or a polypeptide comprising an amino acid sequence with substitution, deletion or insertion of one or more amino acids in the amino acid sequence shown in SEQ ID NO: 27 or 28; and (f) a polypeptide comprising an amino acid sequence with 80% or higher identity to the amino acid sequence shown in SEQ ID NO: 27 or 28. [13-6-4] The method according to [13-2-1], [13-2-2], [13-3], [13-4] or [13-6-3] above, wherein a polypeptide constituting the fusion protein and a polynucleotide constituting the fusion gene are any of the following polypeptides (a) to (f) and any of polynucleotides encoding the polypeptides: (a) a polypeptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24; (b) a polypeptide which comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24 and which carriers activated tyrosine kinase, or a polypeptide which comprises an amino acid sequence with substitution, deletion or insertion of 1 to 10 amino acids in an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24 and which has tyrosine kinase activity; (c) a polypeptide which comprises an amino acid sequence with 90% or higher identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24 and which has tyrosine kinase activity; (d) a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 27 or 28; (e) a polypeptide which comprises the amino acid sequence shown in SEQ ID NO: 27 or 28 and which carries activated RET tyrosine kinase, or a polypeptide which comprises an amino acid sequence with substitution, deletion or insertion of 1 to 10 amino acids in the amino acid sequence shown in SEQ ID NO: 27 or 28 and which has tyrosine kinase activity; and (f) a polypeptide which comprises an amino acid sequence with 90% or higher identity to the amino acid sequence shown in SEQ ID NO: 27 or 28 and which has tyrosine kinase activity. [13-7] The method according to [13-6] above, wherein the fusion gene is any of (a) to (d) shown below: (a) a fusion gene which comprises a polynucleotide having a nucleotide sequence selected from the group consisting of SEQ ID NOs: 5 to 14; (b) a fusion gene consisting of a polynucleotide which hybridizes under stringent conditions to DNA consisting of a nucleotide sequence complementary to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 5 to 14 and which encodes a polypeptide having tyrosine kinase activity; (c) a fusion gene which comprises a polynucleotide encoding a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24; or (d) a fusion gene comprising a polynucleotide encoding a polypeptide which has substitution, deletion or insertion of one or more (e.g., several tens, 1 to 10, 1 to 5, 1 to 3) amino acids in a polypeptide having an amino acids sequence selected from the group consisting of SEQ ID NOs: 15 to 24 and which has tyrosine kinase activity. [13-8] The method according to [13] to [13-2] above, wherein the tissue has a point mutation in RET. [13-9] The method according to [13-8] above, wherein the tissue has a point mutation in the cysteine-rich domain or in the tyrosine kinase domain of RET tyrosine kinase. [13-10] The method according to [13-8] or [13-9] above, wherein the point mutation is a mutation in the nucleotide 2091G, 2261G, 2494G, 2562A, 2600G, 2861T or 29431T of a polynucleotide having the nucleotide sequence shown in SEQ ID NO: 1. [13-10-1] The method according to any one of [13-8] to [13-10] above, wherein the point mutation is a mutation in the nucleotide 2091G, 2261G, 2494G, 2562A or 2861T of a polynucleotide having the nucleotide sequence shown in SEQ ID NO: 1. [13-11] The method according to any one of [13-8] to [13-10] above, wherein the point mutation is a mutation in the nucleotide 2091 G, 2494G, 2600G or 2943T of a polynucleotide having the nucleotide sequence shown in SEQ ID NO: 1. [13-12] The method according to any one of [13-8] to [13-10] above, wherein the point mutation is 2091G>T, 2261G>A, 2494G>C, 2562A>T, 2600G>A, 2600G>C, 2861 T>G or 2943T>C in a polynucleotide having the nucleotide sequence shown in SEQ ID NO: 1. [13-12-1] The method according to any one of [13-8] to [13-10] and [13-12] above, wherein the point mutation is 2091G>T, 2261G>A, 2494G>C, 2562A>T or 2861T>G in a polynucleotide having the nucleotide sequence shown in SEQ ID NO: 1. [13-13] The method according to any one of [13-8] to [13-12] above, wherein the point mutation is 2091G>T, 2494G>C, 2600G>A or 2943T>C in a polynucleotide having the nucleotide sequence shown in SEQ ID NO: 1. [13-14] The method according to [13-8] or [13-9] above, wherein the point mutation is a mutation in the amino acid C609, C611, C618, C620, C630, C634, G691, E768, Y791, V804, S891, A883 or M918 of a polypeptide having the amino acid sequence shown in SEQ ID NO: 3. [13-14-1] The method according to [13-8], [13-9] or [13-14] above, wherein the point mutation is a mutation in the amino acid C609, C611, C618, C620, C630, C634, G691, E768, Y791, 5891 or A883 of a polypeptide having the amino acid sequence shown in SEQ ID NO: 3. [13-15] The method according to [13-8], [13-9] or [13-14] above, wherein the point mutation is a mutation in the amino acid C609, C611, C618, C620, C630, C634, E768, V804, S891, A883 or M918 of a polypeptide having the amino acid sequence shown in SEQ ID NO: 3. [13-16] The method according to [13-8], [13-9] or [13-14] above, wherein the point mutation is C634W, C634Y, G691S, E768D, Y791F, V804M, V804L, S891A or M918T in a polypeptide having the amino acid sequence shown in SEQ ID NO: 3. [13-16-1] The method according to [13-8], [13-9] or [13-14] above, wherein the point mutation is C634W, C634Y, G691S, E768D, Y791F or S891A in a polypeptide having the amino acid sequence shown in SEQ ID NO: 3. [13-17] The method according to any one of [13-8] to [13-16] above, wherein the point mutation in RET is C634Y, E768D, V804M or M918T in a polypeptide having the amino acid sequence shown in SEQ ID NO: 3. [13-18] The method according to any one of [13] to [13-17] above, wherein the method identifies a subject to be administered with a compound represented by formula (I), a salt thereof or a solvate thereof for treatment and/or prevention of a tumor with a mutation in RET or metastasis of the tumor. [13-19] The method according to any one of [13] to [13-18] above, wherein the tumor is thyroid cancer or lung cancer. [13-20] The method according to any one of [13] to [13-19] above, wherein the compound represented by formula (I), the salt thereof or the solvate thereof selectively inhibits RET. [13-21] The method according to any one of [13] to [13-20] above, wherein R1 is ethyl. [13-22] The method according to any one of [13] to [13-21] above, wherein the compound of formula (I), the salt thereof or the solvate thereof is hydrochloride of the compound of formula (I). [14]A prophylactic and/or therapeutic method for a tumor with a mutation in RET and for metastasis of the tumor, which comprises identifying a patient with a mutation in RET and administering the patient with an effective therapeutic amount of a compound represented by formula (I), a salt thereof or a solvate thereof. [15]A method for identifying or preliminarily identifying a patient sensitive to a compound represented by formula (I), a salt thereof or a solvate thereof, which comprises the steps of: detecting the presence of a mutation in RET in a sample obtained from the patient; and determining or preliminarily determining that the patient has sensitivity to the compound, the salt thereof or the solvate thereof, on the basis of the presence of a mutation in RET in the sample. [15-1] The method according to [15] above, further comprising the step of detecting activation of RET tyrosine kinase. [15-2] The method according to [15] above, wherein the mutation in RET is a mutation which induces activation of RET tyrosine kinase. [15-2-1] The method according to any one of [15] to [15-2] above, wherein the mutation in RET is (a) a mutation in the cysteine-rich domain of RET tyrosine kinase, (b) a mutation in the tyrosine kinase domain of RET tyrosine kinase, or (c) the formation of a fusion gene of RET and/or a fusion protein of RET. [15-2-2] The method according to any one of [15] to [15-2-1] above, wherein the mutation in RET results in the formation of a fusion gene of RET and/or a fusion protein of RET. [15-2-3] The method according to any one of [15] to [15-2-2] above, wherein the mutation in RET results in the formation of KIF5B-RET, CCDC6-RETI, NCOA4-RET or TRIM33-RET. [15-3] The method according to any one of [15] to [15-2] above, wherein the mutation in RET is (a) a mutation in the cysteine-rich domain of RET tyrosine kinase, (b) a mutation in the tyrosine kinase domain of RET tyrosine kinase, or (c) the formation of a fusion gene between RET gene and another gene and/or a fusion protein between RET protein and another protein. [15-4] The method according to any one of [15] to [15-3] above, wherein the mutation in RET results in the formation of a fusion gene between RET gene and another gene and/or a fusion protein between RET protein and another protein. [15-5] The method according to [15-4] above, wherein the other gene and protein are KIF5B, CCDC6, NCOA4 or TRIM33. [15-6] The method according to [15-4] or [15-5] above, wherein the fusion gene between RET gene and another gene and the fusion protein between RET protein and another protein comprise the tyrosine kinase domain of RET gene or protein and the coiled-coil domain of another gene or protein. [15-6-1] The method according to any one of [15-4] to [15-6] above, wherein a polypeptide constituting the RET protein and a polynucleotide constituting the RET gene are any of the following polypeptides and any of polynucleotides encoding the polypeptides: (a) a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 3 or 4; (b) a polypeptide consisting of an amino acid sequence with substitution, deletion or insertion of one or more amino acids in the polypeptide shown in SEQ ID NO: 3 or 4; and (c) a polypeptide consisting of an amino acid sequence with 80% or higher identity to the amino acid sequence shown in SEQ ID NO: 3 or 4. [15-6-2] The method according to [15-5] above, wherein a polypeptide constituting each of the KIF5B, CCDC6, NCOA4 and TRIM33 proteins and a polynucleotide constituting each of the KIF5B, CCDC6, NCOA4 and TRIM33 genes are any of the following polypeptides and any of polynucleotides encoding the polypeptides:
(1) the polypeptide constituting the KIF5B protein is (a) a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 30, (b) a polypeptide consisting of an amino acid sequence with substitution, deletion or insertion of one or more amino acids in the amino acid sequence shown in SEQ ID NO: 30, or (c) a polypeptide consisting of an amino acid sequence with 80% or higher identity to the amino acid sequence shown in SEQ ID NO: 30; (2) the polypeptide constituting the CCDC6 protein is (a) a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 31, (b) a polypeptide consisting of an amino acid sequence with substitution, deletion or insertion of one or more amino acids in the amino acid sequence shown in SEQ ID NO: 31, or (c) a polypeptide consisting of an amino acid sequence with 80% or higher identity to the amino acid sequence shown in SEQ ID NO: 31; (3) the polypeptide constituting the NCOA4 protein is (a) a polypeptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 38 to 42, (b) a polypeptide consisting of an amino acid sequence with substitution, deletion or insertion of one or more amino acids in an amino acid sequence selected from the group consisting of SEQ ID NOs: 38 to 42, or (c) a polypeptide consisting of an amino acid sequence with 80% or higher identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 38 to 42; and (4) the polypeptide constituting the TRIM33 protein is (a) a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 45 or 46, (b) a polypeptide consisting of an amino acid sequence with substitution, deletion or insertion of one or more amino acids in the amino acid sequence shown in SEQ ID NO: 45 or 46, or (c) a polypeptide consisting of an amino acid sequence with 80% or higher identity to the amino acid sequence shown in SEQ ID NO: 45 or 46. [15-6-3] The method according to [15-2-1], [15-2-2], [15-3] or [15-4] above, wherein a polypeptide constituting the fusion protein and a polynucleotide constituting the fusion gene are any of the following polypeptides (a) to (f) and any of polynucleotides encoding the polypeptides: (a) a polypeptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24; (b) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24, or a polypeptide comprising an amino acid sequence with substitution, deletion or insertion of one or more amino acids in an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24; (c) a polypeptide comprising an amino acid sequence with 80% or higher identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24; (d) a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 27 or 28; (e) a polypeptide comprising the amino acid sequence shown in SEQ ID NO: 27 or 28, or a polypeptide comprising an amino acid sequence with substitution, deletion or insertion of one or more amino acids in the amino acid sequence shown in SEQ ID NO: 27 or 28; and (f) a polypeptide comprising an amino acid sequence with 80% or higher identity to the amino acid sequence shown in SEQ ID NO: 27 or 28. [15-6-4] The method according to [15-2-1], [15-2-2], [15-3] or [15-4] above, wherein a polypeptide constituting the fusion protein and a polynucleotide constituting the fusion gene are any of the following polypeptides (a) to (f) and any of polynucleotides encoding the polypeptides: (a) a polypeptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24; (b) a polypeptide which comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24 and which carriers activated tyrosine kinase, or a polypeptide which comprises an amino acid sequence with substitution, deletion or insertion of 1 to 10 amino acids in an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24 and which has tyrosine kinase activity; (c) a polypeptide which comprises an amino acid sequence with 90% or higher identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24 and which has tyrosine kinase activity; (d) a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 27 or 28; (e) a polypeptide which comprises the amino acid sequence shown in SEQ ID NO: 27 or 28 and which carries activated RET tyrosine kinase, or a polypeptide which comprises an amino acid sequence with substitution, deletion or insertion of 1 to 10 amino acids in the amino acid sequence shown in SEQ ID NO: 27 or 28 and which has tyrosine kinase activity; and (f) a polypeptide which comprises an amino acid sequence with 90% or higher identity to the amino acid sequence shown in SEQ ID NO: 27 or 28 and which has tyrosine kinase activity. [15-6-5] The method according to [15-3] or [15-4] above, wherein the fusion gene is any of (a) to (d) shown below: (a) a fusion gene which comprises a polynucleotide having a nucleotide sequence selected from the group consisting of SEQ ID NOs: 5 to 14; (b) a fusion gene consisting of a polynucleotide which hybridizes under stringent conditions to DNA consisting of a nucleotide sequence complementary to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 5 to 14 and which encodes a polypeptide having tyrosine kinase activity; (c) a fusion gene which comprises a polynucleotide encoding a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24; or (d) a fusion gene comprising a polynucleotide encoding a polypeptide which has substitution, deletion or insertion of one or more (e.g., several tens, 1 to 10, 1 to 5, 1 to 3) amino acids in a polypeptide having an amino acids sequence selected from the group consisting of SEQ ID NOs: 15 to 24 and which has tyrosine kinase activity. [15-7] The method according to any one of [15] to [15-2] above, wherein the mutation in RET is a point mutation. [15-8] The method according to [15-7] above, wherein the point mutation is a point mutation in the cysteine-rich domain or in the tyrosine kinase domain of RET tyrosine kinase. [15-9] The method according to [15-7] or [15-8] above, wherein the point mutation is a mutation in the nucleotide 2091G, 2261G, 2494G, 2562A, 2600G, 2861T or 2943T of a polynucleotide having the nucleotide sequence shown in SEQ ID NO: 1. [15-9-1] The method according to any one of [15-7] to [15-9] above, wherein the point mutation is a mutation in the nucleotide 2091G. 2261G, 2494G, 2562A or 286 IT of a polynucleotide having the nucleotide sequence shown in SEQ ID NO: 1. [15-10] The method according to any one of [15-7] or [15-9] above, wherein the point mutation is a mutation in the nucleotide 2091G, 2494G, 2600G or 2943T of a polynucleotide having the nucleotide sequence shown in SEQ ID NO: 1. [15-11] The method according to any one of [15-7] to [15-9] above, wherein the point mutation is 2091G>T, 2261 G>A, 2494G>C, 2562A>T, 2600G>A, 2600G>C, 2861T>G or 2943T>C in a polynucleotide having the nucleotide sequence shown in SEQ ID NO: 1. [15-11-1] The method according to any one of [15-7] to [15-9-1] and [15-1] above, wherein the point mutation is 2091G>T, 2261G>A, 2494G>C, 2562A>T or 2861T>G in a polynucleotide having the nucleotide sequence shown in SEQ ID NO: 1. [15-12] The method according to any one of [15-7] to [15-11] above, wherein the point mutation is 2091G>T, 2494G>C, 2600G>A or 2493T>C in a polynucleotide having the nucleotide sequence shown in SEQ ID NO: 1. [15-13] The method according to [15-7] or [15-8] above, wherein the point mutation is a mutation in the amino acid C609, C611, C618, C620, C630, C634, G691, E768, Y791, V804, 5891, A883 or M918 of a polypeptide having the amino acid sequence shown in SEQ ID NO: 3. [15-13-1] The method according to [15-7], [15-8] or [15-13] above, wherein the point mutation is a mutation in the amino acid C609, C611, C618, C620, C630, C634, G691, E768, Y791, 5891 or A883 of a polypeptide having the amino acid sequence shown in SEQ ID NO: 3. [15-14] The method according to [15-7], [15-8] or [15-13] above, wherein the point mutation is a mutation in the amino acid C609, C611, C618, C620, C630, C634, E768, V804, S891, A883 or M918 of a polypeptide having the amino acid sequence shown in SEQ ID NO: 3. [15-15] The method according to [15-7], [15-8] or [15-13] above, wherein the point mutation is C634W, C634Y, G691S, E768D, Y791F, V804M, V804L, S891A or M918T in a polypeptide having the amino acid sequence shown in SEQ ID NO: 3. [15-15-1] The method according to [15-7], [15-8], [15-13] or [15-15] above, wherein the point mutation is C634W, C634Y, G691S, E768D, Y791F or S891A in a polypeptide having the amino acid sequence shown in SEQ ID NO: 3. [15-16] The method according to any one of [15-7] to [15-15], wherein the point mutation is C634W, C634Y, E768D, V804M or M918T in a polypeptide having the amino acid sequence shown in SEQ ID NO: 3. [15-17] The method according to any one of [15] to [15-16] above, wherein the patient is a patient with thyroid cancer or lung cancer. [15-18] The method according to any one of [15] to [15-17] above, wherein the patient is a patient with thyroid medullary cancer or non-small cell lung cancer. [15-19] The method according to any one of [15] to [15-18] above, wherein the compound of formula (I), the salt thereof or the solvate thereof selectively inhibits RET. [15-20] The method according to any one of [15] to [15-18] above, wherein R1 is ethyl. [15-21] The method according to any one of [15] to [15-19] above, wherein the compound is a hydrochloride. [16]A method for predicting the sensitivity of a patient to a compound of formula (I), a salt thereof or a solvate thereof, which comprises the steps of; (1) confirming the presence or absence of a mutation in RET in a sample obtained from the patient; and (2) determining or preliminarily determining that the patient has sensitivity to the compound of formula (I), the salt thereof or the solvate thereof, provided that the mutation in RET is present.
Effects of the Invention
[0022] The therapeutic and/or prophylactic agent of the present invention has a potent inhibitory effect against RET, particularly against RET tyrosine kinase, and is useful as a prophylactic or therapeutic agent (particularly therapeutic agent) for proliferative diseases. Moreover, the active ingredient in the present invention is useful as a prophylactic or therapeutic agent (particularly therapeutic agent) for diseases including various types of cancers, such as leukemia (e.g., acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia), malignant lymphoma (e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma), brain tumor, neuroblastoma, glioma, thyroid cancer, myelodysplastic syndrome, head and neck cancer, esophageal cancer, gastric cancer, colorectal cancer, breast cancer, ovarian cancer, lung cancer, pancreatic cancer, liver cancer, gallbladder cancer, skin cancer, malignant melanoma, kidney cancer, renal pelvic and ureteral cancer, bladder cancer, uterine cancer, testicular cancer and prostate cancer. The active ingredient in the present invention is further useful as a prophylactic or therapeutic agent (particularly therapeutic agent) for infiltration and metastasis of solid cancers.
[0023] The present invention achieves the identification of a cancer or a patient with a mutation in RET and achieves the effective treatment, etc. of such a patient using the compound represented by formula (I) or the like.
BRIEF DESCRIPTION OF THE DRAWING
[0024] FIG. 1 shows the antitumor activity of compound 1 using xenograft mouse models having CCDC6-RET fusion gene (Example 6).
MODE FOR CARRYING OUT THE INVENTION
[0025] An explanation will be given below of the therapeutic or prophylactic agent of the present invention and preparation procedures thereof.
DEFINITIONS
[0026] In the context of the present invention, the term "C1-6 alkyl group" refers to a monovalent group derived from a linear or branched aliphatic hydrocarbon containing 1 to 6 carbon atoms by removing any one of the hydrogen atoms. More specifically, examples include a methyl group, an ethyl group, an isopropyl group, a butyl group, a n-butyl group, an isobutyl group, a sec-butyl group, a t-butyl group, a pentyl group, an isopentyl group, a 2,3-dimethylpropyl group, a hexyl group, a 2,3-dimethylhexyl group, a 1,1-dimethylpentyl group, a heptyl group and an octyl group. Preferred is a C1-6 alkyl group, more preferred is a C1-5 alkyl group, even more preferred is a C1-4 alkyl group, and still even more preferred is a C1-3 alkyl group.
[0027] In the context of the present invention, the expression "with a mutation in RET", "a mutation in RET" or "a mutation of RET" is intended to mean that a mutation occurs in RET gene and/or RET protein. In the context of the present invention, the expression "with a mutation in RET", "a mutation in RET" includes a point mutation, a deletion mutation or an insertion mutation in RET gene and/or RET protein, translocation- or inversion-mediated fusion between RET gene and another gene, as well as fusion protein formation between RET protein and another protein. The expression "with a mutation in RET", "a mutation in RET" or "a mutation of RET" further includes amplification of RET gene and/or amplification of RET protein, caused by an increased number of DNA regions on the genome compared to the normal state upon cleavage and rejoining of RET gene, impairment in the repair functions for RET gene, etc.
[0028] In the context of the present invention, the term "RET gene" is intended to mean a gene encoding RET (rearranged during transfection) tyrosine kinase. The RET gene of the present invention is intended to mean RET gene of any origin. Specifically, examples include, but are not limited to, a gene having a polynucleotide consisting of the nucleotide sequence shown in SEQ ID NO: 1 or 2, and a polynucleotide encoding a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 3 or 4.
[0029] In the context of the present invention, the term "RET protein" is intended to mean a protein consisting of an amino acid sequence constituting RET tyrosine kinase. The RET protein of the present invention is intended to mean RET protein of any origin. Specifically, examples include, but are not limited to, a protein having a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 3 or 4. It is known that there are three types of proteins RET9, RET43 and RET51 for RET tyrosine kinase due to differences in carboxyl-terminal splicing (TRENDS in Genetics. 2006, vol. 22, p. 627-636), and polypeptides consisting of amino acids constituting these three types of proteins also fall within "RET protein."
[0030] In the present invention, the polypeptide constituting the RET protein and the polynucleotide constituting the RET gene include the following polypeptides and genes encoding the polypeptides:
[0031] a polypeptide consisting of an amino acid sequence with substitution, deletion or insertion of one or more (preferably 1 to 10, particularly preferably 1 to 5) amino acids in the polypeptide shown in SEQ ID NO: 3 or 4: and
[0032] a polypeptide consisting of an amino acid sequence with 80% or higher (preferably 85% or higher, more preferably 90% or higher, further preferably 95% or higher) identity to the amino acid sequence shown in SEQ ID NO: 3 or 4.
[0033] In the context of the present invention, the expression "polynucleotide encoding a polypeptide" encompasses every polynucleotide capable of encoding a specific polypeptide and encompasses any of genomic DNA and cDNA. The polynucleotide includes even a degenerate polynucleotide composed of any codon encoding the same amino acid.
[0034] In the present invention, the identity of an amino acid sequence can be calculated by: properly aligning at least two sequences to be compared with each other; determining identical amino acid residues between the sequences; determining the number of matching sites; and subsequently dividing the number of the matching sites by the total number of residues in the sequence region to be compared and multiplying the obtained numeric value by 100. For example, the identity of a specific amino acid sequence to the amino acid sequence shown in SEQ ID NO: 3 can be calculated by: determining the number of matching sites between two sequences, i.e., the amino acid sequence shown in SEQ ID NO: 3 and the specific amino acid sequence, by the above method; and subsequently dividing the number of the matching sites by the total number of residues in the amino acid sequence shown in SEQ ID) NO: 3 and multiplying the obtained numeric value by 100.
[0035] Alternatively, the identity of an amino acid sequence may be determined by the Karlin-Altschul BLAST algorithm (Proc. Natl. Acad. Sci. USA (1993) 90: 5873-7). On the basis of this algorithm, a program called BLASTN or BLASTX has been developed (Altschul et al., J. Mol. Biol. (1990) 215: 403-10). Each nucleotide sequence can be analyzed by BLASTN on the basis of BLAST using parameters set to, for example, score=100 and wordlength=12. Also, each amino acid sequence can be analyzed by BLASTX on the basis of BLAST using parameters set to, for example, score=50 and wordlength=3. In the case of using BLAST and Gapped BLAST programs, the default parameters of each program are used. Specific approaches of these analysis methods are known in the art (see information provided by the website of BLAST (Basic Local Alignment Search Tool), NCBI (National Center for Biotechnology Information)).
[0036] In the context of the present invention, the term "hybridizing" is intended to mean hybridizing to a target DNA or polynucleotide under stringent conditions. The stringent conditions can be determined on the basis of the melting temperature (Tm) of a nucleic acid to form a complex according to a routine method. Specifically, the stringent conditions involve "5×SSPE, 5×Denhardt's solution, 0.5% SDS, 50% formamide, 200 μg/ml salmon sperm DNA, 42° C. overnight" as conditions for hybridization and "0.5×SSC, 0.1% SDS, 42° C." as conditions for washing. More stringent conditions involve "5×SSPE, 5×Denhardt's solution, 0.5% SDS, 50% formamide, 200 μg/ml salmon sperm DNA, 42° C. overnight" as conditions for hybridization and "0.2×SSC, 0.1% SDS, 65° C." as conditions for washing.
[0037] The expression "with a mutation in RET", "a mutation in RET" or "a mutation of RET" further includes a state where a mutation which induces activation of RET tyrosine kinase or a mutation which activates RET tyrosine kinase and induces oncogenesis (e.g., thyroid cancer, lung cancer) has occurred in RET gene and/or RET protein. The activation of RET tyrosine kinase can be confirmed by detecting phosphorylated RET in a tumor tissue by immunostaining or the like using an anti-phosphorylated RET antibody.
[0038] In the context of the present invention, the expression "activation of RET tyrosine kinase" or "state where RET tyrosine kinase has been activated" is intended to mean that an amino acid residue (e.g., a tyrosine residue) contained in RET tyrosine kinase has been phosphorylated, and includes the amount of phosphorylated RET tyrosine kinase protein is increased in a subject (e.g., a sample taken from a subject) (e.g., when compared to a normal subject). In addition, the expression "activation of RET tyrosine kinase" or "state where RET tyrosine kinase has been activated" includes a state where phosphorylated RET tyrosine kinase induces phosphorylation of a protein serving as a target of RET tyrosine kinase (hereinafter referred to as a target protein). The expression "activation of RET tyrosine kinase" or "state where RET tyrosine kinase has been activated" include not only the amount of phosphorylated RET tyrosine kinase protein, but also the amount of the above target protein in a phosphorylated form is increased.
[0039] In the context of the present invention, the expression "having tyrosine kinase activity" is intended to mean having activity as an enzyme that phosphorylates an amino acid residue, for example, a tyrosine residue, contained in tyrosine kinase. The tyrosine kinase activity of a polypeptide constituting the RET protein can be confirmed by, for example, the above method. In addition, the expression "having tyrosine kinase activity" includes having activity as an enzyme that phosphorylates an amino acid residue of a targeted protein.
[0040] Mutations reported to induce activation of RET tyrosine kinase include (1) a mutation in the cysteine-rich domain of RET, (2) a mutation in the tyrosine kinase domain of RET, and (3) formation of a fusion gene between RET gene and another gene or a fusion protein between RET protein and another protein (TRENDS in Genetics, 2006, vol. 22, p. 627-636). The human RET gene is located on chromosome 10 (10q1.2) and composed of 21 exons. The "cysteine-rich domain of RET" refers to a region rich in cysteine found in RET tyrosine kinase, and a polynucleotide encoding this domain is located at exons 10 and 11. The "tyrosine kinase domain of RET" refers to a region having tyrosine kinase activity found in RET tyrosine kinase, and a polynucleotide encoding this domain is located at exons 12 to 18 (TRENDS in Genetics, 2006, vol. 22, p. 627-636).
[0041] Specific examples of the above mutations (1) to (3) include those listed below. In the context of the present invention, the expression "with a mutation in RET" or "a mutation in RET" includes a state where any of these mutations (1) to (3) has occurred in RET gene and/or RET protein.
(1) Mutation in the Cysteine-Rich Domain
[0042] A mutation in C609, C611, C618, C620, C630, C634 or elsewhere in the amino acid sequence shown in SEQ ID NO: 3 (e.g., C634W, C634Y)
(2) Mutation in the Tyrosine Kinase Domain
[0043] A mutation in E768, V804, S891, A883, M918 or elsewhere in the amino acid sequence shown in SEQ ID NO: 3 (e.g., E768D. V804M, V804L, M918T)
(3) Formation of a Fusion Gene Between RET Gene and Another Gene or a Fusion Protein Between RET Protein and Another Protein
[0044] Formation of KIF5B-RET fusion gene and/or fusion protein comprising the coiled-coil domain of KIF5B and the tyrosine kinase domain of RET
[0045] Formation of CCDC6-RET fusion gene and/or fusion protein comprising the coiled-coil domain of CCDC6 and the tyrosine kinase domain of RET
[0046] Formation of NCOA4-RET fusion gene and/or fusion protein comprising the coiled-coil domain of NCOA4 and the tyrosine kinase domain of RET
[0047] Formation of TRIM33-RET fusion gene and/or fusion protein comprising the coiled-coil domain of TRIM33 and the tyrosine kinase domain of RET
[0048] In the context of the present invention, the expression "gene of KIF5B" or "KIF5B gene" is intended to mean a gene encoding KIF5B (Kinesin family protein 5B), and the expression "protein of KIF5B" or "KIF5B protein" is intended to mean a protein consisting of an amino acid sequence constituting KIF5B. These terms are intended to mean a gene or a protein of KIF5B of any origin. Examples of a polynucleotide constituting the KIF5B gene and a polypeptide constituting the KIF5B protein specifically include, but are not limited to, a polynucleotide consisting of the nucleotide sequence shown in SEQ ID NO: 29 and a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 30. The polypeptide constituting the KIF5B protein and the polynucleotide constituting the KIF5B gene further include the following polypeptides and polynucleotides encoding the polypeptides:
[0049] a polypeptide consisting of an amino acid sequence with substitution, deletion or insertion of one or more (preferably 1 to 10, particularly preferably 1 to 5) amino acids in the amino acid sequence shown in SEQ ID NO: 30; and
[0050] a polypeptide consisting of an amino acid sequence with 80% or higher (preferably 85% or higher, more preferably 90% or higher, further preferably 95% or higher) identity to the amino acid sequence shown in SEQ ID NO: 30.
[0051] The human KIF5B gene is located in chromosome 10 and composed of 26 exons. Candidates for the nucleotide sequence of KIF5B-RET fusion gene include, but are not limited to, those shown in SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11. SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14. Candidates for the amino acid sequence of KIF5B-RET fusion protein include, but are not limited to, those shown in SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23 and SEQ ID NO: 24. Such KIF5B-RET fusion gene and fusion protein are reported to comprise the coiled-coil domain of KIF5B and the kinase domain of RET (Nature Medicine. 2012, 18, p. 378-381, Nature Medicine. 2012, 18, p. 382-384). In the present invention, the polypeptide constituting the KIF5B-RET fusion protein and the polynucleotide constituting the KIF5B-RET fusion gene additionally include the following polypeptides and polynucleotides encoding the polypeptides:
(i) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24, or a polypeptide comprising an amino acid sequence with substitution, deletion or insertion of one or more (preferably 1 to 10, particularly preferably 1 to 5) amino acids in an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24; (ii) a polypeptide comprising an amino acid sequence with 80% or higher (preferably 85% or higher, more preferably 90% or higher, further preferably 95% or higher) identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 24; and (iii) a polypeptide which is the polypeptide (i) or (ii) and which has tyrosine kinase activity.
[0052] In the context of the present invention, the expression "gene of CCDC6" or "CCDC6 gene" is intended to mean a gene encoding CCDC6 (coiled-coil domain containing 6), and the expression "protein of CCDC6" or "CCDC6 protein" is intended to mean a protein consisting of an amino acid sequence constituting CCDC6. These terms are intended to mean a gene or a protein of CCDC6 of any origin. Examples of a polynucleotide constituting the CCDC6 gene and a polypeptide constituting the CCDC6 protein specifically include, but are not limited to, a polynucleotide consisting of the nucleotide sequence shown in SEQ ID NO: 31 and a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 32. The polypeptide constituting the CCDC6 protein and the polynucleotide constituting the CCDC6 gene further include the following polypeptides and polynucleotides encoding the polypeptides:
[0053] a polypeptide consisting of an amino acid sequence with substitution, deletion or insertion of one or more (preferably 1 to 10, particularly preferably 1 to 5) amino acids in the amino acid sequence shown in SEQ ID NO: 31; and
[0054] a polypeptide consisting of an amino acid sequence with 80% or higher (preferably 85% or higher, more preferably 90% or higher, further preferably 95% or higher) identity to the amino acid sequence shown in SEQ ID NO: 31.
[0055] Human CCDC6 is located in chromosome 10 and composed of 9 exons.
[0056] Examples of the nucleotide sequence of CCDC6-RET fusion gene include, but are not limited to, those shown in SEQ ID NOs: 25 and 26. Examples of the amino acid sequence of the CCDC6-RET fusion protein include, but are not limited to, those shown in SEQ ID NOs: 27 and 28. Such CCDC6-RET fusion gene and fusion protein are reported to comprise the coiled-coil domain of CCDC6 and the tyrosine kinase domain of RET (Nat Med. 2012 Feb. 12; 18 (3): 378-81).
[0057] Examples of the polypeptide constituting the CCDC6-RET fusion protein and the polynucleotide constituting the CCDC6-RET fusion gene additionally include the following polypeptides and polynucleotides encoding the polypeptides:
(i) a polypeptide comprising the amino acid sequence shown in SEQ ID NO: 27 or 28, or a polypeptide comprising an amino acid sequence with substitution, deletion or insertion of one or more (preferably 1 to 10, particularly preferably 1 to 5) amino acids in the amino acid sequence shown in SEQ ID NO: 27 or 28; (ii) a polypeptide comprising an amino acid sequence with 80% or higher (preferably 85% or higher, more preferably 90% or higher, further preferably 95% or higher) identity to the amino acid sequence shown in SEQ ID NO: 27 or 28; and (iii) a polypeptide which is the polypeptide (i) or (ii) and which has tyrosine kinase activity.
[0058] In the context of the present invention, the expression "gene of NCOA4" or "NCOA4 gene" is intended to mean a gene encoding NCOA4 (nuclear receptor coactivator 4), and the expression "protein of NCOA4" or "NCOA4 protein" is intended to mean a protein consisting of an amino acid sequence constituting NCOA4. These terms are intended to mean a gene or a protein of NCOA4 of any origin. Examples of a polynucleotide constituting the NCOA4 gene and a polypeptide constituting the NCOA4 protein specifically include, but are not limited to, a polynucleotide consisting of a nucleotide sequence selected from the group consisting of SEQ ID NOs: 33 to 37 and a polypeptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 38 to 42. The polypeptide constituting the NCOA4 protein and the polynucleotide constituting the NCOA4 gene further include the following polypeptides and polynucleotides encoding the polypeptides:
[0059] a polypeptide consisting of an amino acid sequence with substitution, deletion or insertion of one or more (preferably 1 to 10, particularly preferably 1 to 5) amino acids in an amino acid sequence selected from the group consisting of SEQ ID NOs: 38 to 42; and
[0060] a polypeptide consisting of an amino acid sequence with 80% or higher (preferably 85% or higher, more preferably 90% or higher, further preferably 95% or higher) identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 38 to 42.
[0061] Human NCOA4 is located in chromosome 10. A gene in which NCOA4 exon 6 is fused with RET exon 12 is reported as a NCOA4-RET fusion gene. This fusion gene and its fusion protein are reported to comprise the coiled-coil domain of NCOA4 and the tyrosine kinase domain of RET (J Clin Oncol, 30 (35), Dec. 10, 2012, p. 4352-9).
[0062] In the context of the present invention, the expression "gene of TRIM33" or "TRIM33 gene" is intended to mean a gene encoding TRIM33 (tripartite motif-containing 33), and the expression "protein of TRIM33" or "TRIM33 protein" is intended to mean a protein consisting of an amino acid sequence constituting TRIM33. These terms are intended to mean a gene or a protein of TRIM33 of any origin. Examples of a polynucleotide constituting the TRIM33 gene and a polypeptide constituting the TRIM33 protein specifically include, but are not limited to, a polynucleotide consisting of the nucleotide sequence shown in SEQ ID NO: 43 or 44 and a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 45 or 46. The polypeptide constituting the TRIM33 protein and the polynucleotide constituting the TRIM33 gene further include the following polypeptides and polynucleotides encoding the polypeptides:
[0063] a polypeptide consisting of an amino acid sequence with substitution, deletion or insertion of one or more (preferably 1 to 10, particularly preferably 1 to 5) amino acids in the amino acid sequence shown in SEQ ID NO: 45 or 46; and
[0064] a polypeptide consisting of an amino acid sequence with 80% or higher (preferably 85% or higher, more preferably 90% or higher, further preferably 95% or higher) identity to the amino acid sequence shown in SEQ ID NO: 45 or 46.
[0065] Human TRIM33 is located in chromosome 1. A gene in which TRIM33 exon 14 is fused with RET exon 12 is reported as a TRIM33-RET fusion gene. This fusion gene and its fusion protein are reported to comprise the coiled-coil domain of TRIM33 and the tyrosine kinase domain of RET (Cancer Discov, 3 (6), June 2013, p. 630-5).
[0066] The coiled-coil domain is a domain involved in protein dimerization. KIF5B-RET, CCDC6-RET, NCOA4-RET and TRIM33-RET are therefore considered to form dimers through their coiled-coil domains. These proteins are considered to cause the abnormal activation of RET tyrosine kinase via the dimerization between their coiled-coil domains to induce oncogenesis (Nature Medicine. 2012, 18, p. 378-381: Nature Medicine. 2012, 18, p. 382-384; J Clin Oncol, 30 (35), Dec. 10, 2012, p. 4352-9; and Cancer Discov 2013 June, 3 (6), June 2013, p. 630-5).
[0067] Examples of a mutation in RET protein in thyroid cancer (e.g., thyroid medullary cancer) include C634W, C634Y, E768D, V804M, V804L and M918T mutations in the amino acid sequence shown in SEQ ID NO: 3 (the amino acid sequence of RET). The expressions "C634W," "C634Y," "E768D," "V804M," "V804L" and "M918T" each represent an amino acid mutation, expressed with a numeral representing a specific position which is sandwiched between single-letter symbols of amino acids before and after the mutation. For example, "C634W" denotes a Cys to Trp substitution in the 634th amino acid from the N-terminus of a specific amino acid sequence. Namely, the numeral represents the amino acid position counted from the N-terminus of a specific amino acid sequence, while the single-letter symbols of amino acids appearing before and after the numeral represent amino acids before and after the substitution, respectively.
[0068] Mutations in RET gene corresponding to the above mutations include 2091G>T, 2494G>C, 2600G>A, 2600G>C and 2943T>C mutations in the nucleotide sequence shown in SEQ ID NO: 1 (the nucleotide sequence of RET). The expressions "2091 G>T," "2494G>C," "2600G>A," "2600G>C" and "2943T>C" each represent a nucleotide mutation, expressed with a numeral representing a specific position followed by bases before and after the mutation. For example, "2091G>T" denotes a G to T substitution in the 2091 st nucleotide from the 5' end of a specific base sequence. Namely, the numeral represents the base position counted from the 5' end of a specific base sequence, while the base appearing after the numeral and before the symbol ">" represents a base before the substitution and the base appearing after the symbol ">" represents a base after the substitution.
[0069] Examples of a mutation in RET in lung cancer (e.g., non-small cell lung cancer) include the formation of KIF5B-RET fusion gene and/or protein, CCDC6-RET fusion gene and/or protein, NCOA4-RET fusion gene and/or protein, TRIM33-RET fusion gene and/or protein, etc. More specifically, examples include, but are not limited to, those listed below.
[0070] Formation of KIF5B-RET fusion gene and/or fusion protein comprising the coiled-coil domain of KIF5B and the tyrosine kinase domain of RET
[0071] Formation of CCDC6-RET fusion gene and/or fusion protein comprising the coiled-coil domain of CCDC6 and the tyrosine kinase domain of RET
[0072] Formation of NCOA4-RET fusion gene and/or fusion protein comprising the coiled-coil domain of NCOA4 and the tyrosine kinase domain of RET
[0073] Formation of TRIM33-RET fusion gene and/or fusion protein comprising the coiled-coil domain of TRIM33 and the tyrosine kinase domain of RET
[0074] In the context of the present invention, the expression "fusion gene of RET," "fusion gene between RET gene and another gene" refers to a gene in which all or a part of RET gene is fused with all or a part of another gene (e.g., KIF5B gene, CCIXD6 gene, NCOA4 gene).
[0075] In the context of the present invention, the term "KIF5B-RET fusion gene" refers to a gene in which all or a part of RET gene is fused with all or a part of KIF5B gene. The term "CCDC6-RET fusion gene" refers to a gene in which all or a part of RET gene is fused with all or a part of CCDC6 gene. The term "NCOA4-RET fusion gene" refers to a gene in which all or a part of RET gene is fused with all or a part of NCOA4 gene. The term "TRIM33-RET fusion gene" refers to a gene in which all or a part of RET gene is fused with all or a part of TRIM33 gene.
[0076] In the context of the present invention, the expression "fusion protein of RET," "fusion protein between RET protein and another protein" refers to a protein in which all or a part of RET protein is fused with all or a part of another protein (e.g., KIF5B protein, CCDC6 protein, NCOA4 protein, TRIM33 protein).
[0077] In the context of the present invention, the term "KIF5B-RET fusion protein" refers to a protein in which all or a part of RET protein is fused with all or a part of KIF5B protein. The term "CCDC6-RET fusion protein" refers to a protein in which all or a part of RET protein is fused with all or a part of CCDC6 protein. The term "NCOA4-RET fusion protein" refers to a protein in which all or a part of RET protein is fused with all or a part of NCOA4 protein. The term "TRIM33-RET fusion protein" refers to a protein in which all or a part of RET protein is fused with all or a part of TRIM33 protein.
[0078] In the context of the present invention, the term "KIF5B-RET" is intended to mean KIF5B-RET fusion gene and/or KIF5B-RET fusion protein. The term "CCDC6-RET" is intended to mean CCDC6-RET fusion gene and/or CCDC6-RET fusion protein. The term "NCOA4-RET" is intended to mean NCOA4-RET fusion gene and/or NCOA4-RET fusion protein. The term "TRIM33-RET" is intended to mean TRIM33-RET fusion gene and/or TRIM33-RET fusion protein.
[0079] The expression "tumor with a mutation in RET" is intended to mean a tumor with a mutation in RET gene and/or protein in tumor cells.
[0080] The term "therapeutic agent" is intended to mean a pharmaceutical agent for directly or indirectly ameliorating a target disease or for preventing exacerbations of the target disease. More specifically, it is intended to mean a pharmaceutical agent for use in growth inhibition or size reduction of tumor tissues, inhibition of metastasis, reduction of tumor markers, amelioration of systemic symptoms or extension of survival period in a patient, etc.
[0081] The term "prophylactic agent" is intended to mean a pharmaceutical agent for use in pre-treatment of a patient at risk of suffering from a target disease such that the target disease is not developed.
[0082] The expression "metastasis of the tumor" is intended to mean metastasis of the primary tumor to other tissues. A therapeutic agent for "metastasis of the tumor" is intended to mean a pharmaceutical agent for inhibiting or suppressing metastasis of the tumor, or a pharmaceutical agent for growth inhibition or size reduction of tumor recurring as a result of metastasis. A prophylactic agent for "metastasis of the tumor" is intended to mean a pharmaceutical agent for use in pre-treatment such that the tumor does not metastasize or does not recur as a result of metastasis.
[0083] The expression "tumors metastasized from tumors" is intended to mean that the tumors listed as primary tumors metastasize to other tissues and develop therein.
[0084] The expression "subject to be administered" is intended to mean a subject for which a pharmaceutical agent can be expected to provide a therapeutic effect based on its mechanism of action. More specifically, it is intended to mean a patient with a proliferative disease for which growth inhibition or size reduction of tumor tissues, inhibition of metastasis, reduction of tumor markers, and amelioration of systemic symptoms in the patient can be expected.
[0085] The expression "tissue from the subject" is intended to mean a tissue contained in blood, alveoli, a biopsy sample, a sputum sample or the like taken from a subject such as a patient.
[0086] The expression "patient with a mutation in RET" is intended to mean that the patient has a mutation in RET gene and/or protein either in tumor or non-tumor tissue taken from a patient.
[0087] The term "RET inhibitor" is intended to mean a pharmaceutical agent which inhibits the activity of RET kinase, preferably a pharmaceutical agent which binds to RET kinase and has an inhibitory effect against the activity of RET kinase.
[0088] The expression "selectively inhibiting RET" is intended to mean that inhibitory activity against RET tyrosine kinase is high in terms of IC50 value when compared with inhibitory activity against many other kinases (e.g., ABL, EGFR, FGFR2, HER2, IGFIR, JAKI, KIT, MET, AKTI, MEKl) except for ALK.
[0089] The expression "preliminarily determining" or "preliminarily identifying" is intended to mean providing information about the presence of a mutation in RET in order to determine or identify a sensitive patient.
[0090] In the present invention, the salt of the compound represented by formula (I) includes, for example: hydrochloride, hydrobromide, hydroiodide, phosphate, phosphonate and sulfate; sulfonates such as methanesulfonate and p-toluenesulfonate; carboxylate such as acetate, citrate, malate, tartrate, succinate and salicylate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; and ammonium salts such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt and tetraalkylammonium salt. Preferred examples include hydrochloride and methanesulfonate. Hydrochloride is more preferred.
[0091] Such a salt is produced by contacting the compound with an acid or a base available in pharmaceutical production.
[0092] In the present invention, the compound represented by formula (I) or the salt thereof may be anhydrous or may form a solvate such as a hydrate. The term "solvation" used herein refers to a phenomenon where solute molecules or ions in a solution strongly attract solvent molecules adjacent thereto to create one molecular population and refers to, for example, hydration if the solvent is water. The solvate may be a hydrate or a non-hydrate. An alcohol (e.g., methanol, ethanol, n-propanol), dimethylformamide, or the like can be used as the non-hydrate.
[0093] Also, the compound or the salt thereof used in the present invention can exist in some tautomeric forms, for example, enol and imine forms, keto and enamine forms and mixtures thereof. The tautomers exist as a mixture of tautomeric sets in a solution. One tautomer is usually dominant in a solid form. The expression "one tautomer" in the present invention includes all tautomers of the compound used in the present invention.
[0094] The present invention includes all of stereoisomers (e.g., enantiomers, diastereomers (including cis and trans geometric isomers)) of the compound represented by formula (I), racemates of the isomers and other mixtures. The compound used in the present invention may have, for example, one or more asymmetric points in formula (I). The present invention includes racemic mixtures, diastereomeric mixtures and enantiomers of such compounds.
[0095] The compound according to the present invention may be obtained in a free form. In such a case, the free from can be converted to a salt that may be formed by the compound or to a hydrate or solvate thereof according to a routine method. Alternatively, the compound according to the present invention may be obtained as a salt, hydrate or solvate of the compound. In such a case, these forms can be converted to a free form of the compound according to a routine method.
[0096] Also, a substance used in the present invention includes a prodrug of the compound of formula (I). In this context, the term "prodrug" is intended to mean a derivative of the compound of formula (I) that is converted to the compound of formula (I) or a pharmaceutically acceptable salt thereof through enzymatic or nonenzymatic degradation under physiological conditions after administration. The prodrug may be inactive when administered to a patient, but exists in vivo as the active compound of formula (I) converted therefrom.
[0097] The prodrug, for example, converts to a desired drug form when a specific pH is reached or through the action of an enzyme.
Typical Production Method
[0098] The compound represented by formula (I) that serves as the active ingredient of the therapeutic or prophylactic agent of the present invention can be produced according to a method described in International Publication No. WO2010/143664, though the method for producing the compound represented by formula (I) is not limited thereto.
Therapeutic and/or Prophylactic Agent of the Present Invention
[0099] The term "therapeutic and/or prophylactic agent" used in the present invention refers to a pharmaceutical agent that is used for treatment or prevention or for treatment and prevention and specifically refers to a pharmaceutical agent that is used, for example, for treating or preventing the target disease or for suppressing progression (preventing exacerbations or maintaining the status quo) of the disease state.
[0100] The therapeutic and/or prophylactic agent of the present invention can be used as a pharmaceutical composition comprising a selected compound useful for the present invention and additionally a pharmaceutically acceptable carrier.
[0101] The term "pharmaceutically acceptable carrier" used herein is intended to mean one or more compatible solid or liquid excipients or encapsulating materials that are suitable for administration to mammals. The term "acceptable" used herein is intended to mean that the compound of interest and other ingredients are miscible in a composition in such a manner that reaction substantially reducing the pharmaceutical effectiveness of the composition does not occur therebetween under ordinary use conditions. As a matter of course, the pharmaceutically acceptable carrier must have sufficiently high purity and sufficiently low toxicity suitable for administration to, preferably an animal, more preferably a mammal, to be treated.
[0102] Examples of a material that may be used as the pharmaceutically acceptable carrier include: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethylcellulose sodium, ethylcellulose and methylcellulose; tragacanth gum powder; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; plant oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cacao oil; polyhydric alcohols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifiers such as TWEEN; wetting agents such as lecithin; colorants; flavors; tableting agents; stabilizers; antioxidants; antiseptics; pyrogen-free water; isotonic saline; and phosphate buffer solutions.
[0103] Examples of a method for administering the therapeutic and/or prophylactic agent of the present invention include oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), intracisternal, intravaginal, intraperitoneal, intravesical and local (drip, powder, ointment, gel or cream) routes and inhalation (into oral cavity or using nasal sprays). Examples of the dosage form thereof include: solid preparations such as tablets, capsules, granules, powders and pills; liquid preparations such as aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions charged in containers adapted to division into individual doses; and freeze-dried preparations that can be dissolved in use. Alternatively, the dosage form may be adapted to various administration methods encompassing controlled-release formulations as in subcutaneous implantation.
[0104] These preparations are produced by a well known method using additives such as excipients, lubricants (coating agents), hinders, disintegrants, stabilizers, flavoring agents and diluents.
[0105] Examples of the excipients can include starches such as starch, potato starch and corn starch, lactose, crystalline cellulose and calcium hydrogen phosphate.
[0106] Examples of the coating agents can include ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, shellac, talc, carnauba wax and paraffin.
[0107] Examples of the binders can include polyvinylpyrrolidone, Macrogol and the compounds similar to the excipients.
[0108] Examples of the disintegrants can include compounds similar to the excipients and chemically modified starches and celluloses such as croscarmellose sodium, carboxymethyl starch sodium and cross-linked polyvinylpyrrolidone.
[0109] Examples of the stabilizers can include: p-hydroxybenzoate esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.
[0110] Examples of the flavoring agents can include sweeteners, acidulants and flavors usually used.
[0111] The liquid preparations can be produced using a solvent such as ethanol, phenol, chlorocresol, purified water or distilled water.
[0112] Examples of the surfactants or emulsifiers can include polysorhate 80, polyoxyl 40 stearate, sodium lauryl sulfate and Lauromacrogol.
[0113] The amount of the prophylactic and/or therapeutic agent of the present invention used differs depending on symptom, age, body weight, relative health conditions, the presence of other medications, administration methods, etc. In the case of oral agents, a general effective amount, for example, for a patient (warm-blooded animal, particularly a human) is preferably 0.001 to 3000 mg/kg body weight, more preferably 0.01 to 300 mg/kg body weight, per day in terms of the amount of the active ingredient (compound represented by formula (I)), and the daily dose in an adult patient having a normal body weight is in the range of preferably 1 to 800 mg. In the case of parenteral agents, a general effective amount is preferably 0.001 to 1000 mg/kg body weight, more preferably 0.01 to 300 mg/kg body weight, per day. Desirably, this amount is administered at a single dose or several divided doses per day according to symptom.
[0114] The prophylactic and/or therapeutic agent of the present invention may be formulated by a method described in International Publication No. WO2012/023597.
[0115] The therapeutic and/or prophylactic agent of the present invention may be used in combination with one or more pharmaceutical agents selected from, for example, other chemotherapeutic agents, hormone therapeutic agents, immunotherapeutic agents and molecular target drugs (hereinafter, collectively referred to as concomitant agents). Such an active ingredient may be a low-molecular-weight compound. Alternatively, such an active ingredient may be a low-molecular-weight compound, may be a high-molecular-weight protein, polypeptide or antibody, or may be a vaccine or the like. Moreover, two or more of these active ingredients may be mixed for use at an appropriate ratio.
[0116] Examples of the "chemotherapeutic agents" include alkylating agents, platinum preparations, metabolic antagonists, topoisomerase inhibitors, anticancer antibiotics and plant-derived anticancer agents. Examples of the "alkylating agents" include nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, carboquone, improsulfan tosilate, busulfan, nimustine hydrochloride, mitobronitol, melphalan, dacarbazine, ranimustine, estramustine sodium phosphate, triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman, ethoglucid, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine, pumitepa, ribomustin, temozolomide, treosulfan, trofosfamide, zinostatin stimalamer, adozelesin, cystemustine and bizelesin. Examples of the "platinum preparations" include carboplatin, cisplatin, miboplatin, nedaplatin and oxaliplatin. Examples of the "metabolic antagonists" include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, enocitabine, cytarabine, cytarabine ocfosfate, ancitabine hydrochloride, 5-FU drugs (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur, galocitabine, emitefur), aminopterin, leucovorin calcium, tabloid, butocin, calcium folinate, calcium levofolinate, cladribine, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, piritrexim, idoxuridine, mitoguazone, tiazofurin and ambamustine. Examples of topoisomerase I inhibitors (e.g., irinotecan, topotecan), topoisomerase II inhibitors (e.g., sobuzoxane) and the "anticancer antibiotics" include anthracycline anticancer agents (doxorubicin hydrochloride, daunorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, etc.), actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, neocarzinostatin, mithramycin, sarkomycin, carzinophilin, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride and idarubicin hydrochloride. Examples of the "plant-derived anticancer agents" include vinca alkaloid anticancer agents (vinblastine sulfate, vincristine sulfate, vindesine sulfate, etc.), taxane anticancer agents (paclitaxel, docetaxel, etc.) etoposide, etoposide phosphate, teniposide and vinorelbine.
[0117] Examples of the "hormone therapeutic agents" include adrenocortical hormone drugs (e.g., dexamethasone, prednisolone, betamethasone, triamcinolone). Among them, prednisolone is preferred.
[0118] Examples of the "immunotherapeutic agents (biological response modifiers: BRMs)" include Picibanil, Krestin, sizofiran, lentinan, ubenimex, interferons, interleukins, macrophage colony-stimulating factors, granulocyte colony-stimulating factors, lymphotoxins, BCG vaccines, Corynebacterium parvum, levamisole, polysaccharide K and procodazole.
[0119] The "molecular target drugs" include, for example, "pharmaceutical agents that inhibit the action of cell growth factors and their receptors". The "cell growth factors" may be any substance that promotes cell growth, and examples typically include peptides with a molecular weight of 20,000 or lower which are factors that exert action at lower concentrations through binding to their receptors and specifically include (1) EGF (epidermal growth factor) and substances having substantially the same activity thereas [e.g., EGF, heregulin (HER2 ligand)], (2) insulin and substances having substantially the same activity thereas [e.g., insulin, IGF (insulin-like growth factor)-1, IGF-2], (3) FGF (fibroblast growth factor) and substances having substantially the same activity thereas [e.g., acidic FGF, basic FGF, KGF (keratinocyte growth factor), FGF-10], (4) VEGF (vascular endothelial growth factor) and (5) other cell growth factors [e.g., CSF (colony stimulating factor), EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet-derived growth factor), TGFβ (transforming growth factor β), HGF (hepatocyte growth factor)].
[0120] The "cell growth factor receptors" may be any receptor having the ability to bind to the above cell growth factors, and specific examples include EGF receptors, heregulin receptors (HER2), insulin receptors, IGF receptors, FGF receptor-1 or FGF receptor-2, HGF receptors (c-met), VEGF receptors and SCF receptors (c-kit). Examples of the "pharmaceutical agents that inhibit the action of cell growth factors" include Herceptin (HER2 antibody), GLEEVEC (c-kit, abl inhibitor) and Tarceva (EGF receptor inhibitor).
[0121] The molecular target drugs also include pharmaceutical agents each inhibiting the actions of a plurality of cell growth factors, and pharmaceutical agents that block intracellular signals generated by cell growth factors.
[0122] In addition to the above pharmaceutical agents, L-asparaginase, aceglatone, procarbazine hydrochloride, protoporphyrin-cobalt complex salts, mercury-hematoporphyrin sodium, differentiation inducers (e.g., retinoid, vitamin Ds), angiogenesis inhibitors, α-blockers (e.g., tamsulosin hydrochloride), and the like can also be used.
[0123] Among those described above, a platinum complex (e.g., carboplatin, cisplatin, oxaliplatin), a metabolic antagonist (e.g., gemcitabine, pemetrexed), a topoisomerase I inhibitor (e.g., irinotecan, topotecan), a plant-derived anticancer agent (taxane drugs (e.g., paclitaxel, docetaxel), vinorelbine), an anticancer antibiotic (e.g., mitomycin C), a hormone therapeutic agent (e.g., prednisolone), an immunotherapeutic agent (e.g., Picibanil, Krestin), a molecular target drug (e.g., anti-VEGF antibodies such as bevacizumab, EGFR inhibitors such as erlotinib, VEGFR inhibitors such as sunitinib), or the like is preferred as a concomitant agent. Cisplatin, gemcitabine, paclitaxel, bevacizumab, or the like is more preferred. Alternatively, the therapeutic and/or prophylactic agent of the present invention may be used in combination with a combination therapy using these pharmaceutical agents. Examples include combined use with a combination therapy of cisplatin, vinblastine and mitomycin C, cisplatin and vinorelbine, cisplatin and paclitaxel, cisplatin and gemcitabine, carboplatin and paclitaxel, pemetrexed and cisplatin, or bevacizumab, cisplatin and pemetrexed.
[0124] In the present invention, the timings of administration of the active ingredient of the present invention and the concomitant agent are not limited, and they may be administered simultaneously or at a time interval to a subject to be administered. Alternatively, the active ingredient of the present invention and the concomitant agent may be administered as a single preparation comprising them to a subject to be administered. For example, they may be administered by a multidrug therapy which involves drip-injecting a plurality of drugs in combination over 3 to 6 months or by a method which involves taking oral agents over approximately 2 years.
[0125] Also, a preoperative adjuvant therapy such as "chemotherapy" may be performed before execution of surgery in order to inhibit already spread tumor (cancer) cells to prevent recurrence as a result of metastasis or for the purpose of reducing the extent of surgery.
[0126] A postoperative adjuvant therapy such as "chemotherapy" may be further performed in order to inhibit the growth of tumor (cancer) cells that have not been removed by local treatment such as surgery or radiation to prevent recurrence as a result of metastasis.
[0127] The anticancer agent that may be used in combination with the active ingredient of the present invention may act on not only cancer cells but also normal cells, resulting in the occurrence of adverse reactions. Typical adverse reactions include nausea caused by gastrointestinal mucosal damage, vomiting, anorexia, stomatitis, diarrhea or constipation, taste abnormality, decrease in leukocyte, erythrocyte or platelet level or alopecia caused by bone marrow damage, immune compromise, etc. The active ingredient of the present invention and the concomitant agent may be used in combination with an adverse reaction-reducing agent in order to prevent these adverse reactions. Examples include antiemetics effectively suppressing nausea (e.g., granisetron hydrochloride) and drugs promoting recovery from bone marrow damage (e.g., erythropoietin, G-CSF, GM-CSF).
[0128] The dose of the concomitant agent can be appropriately selected with reference to a dose clinically used. The mixing ratio between the active ingredient of the present invention and the concomitant agent can be appropriately selected according to the subject to be administered, administration routes, the target disease, symptom, combination of the pharmaceutical agents, etc. For example, when the subject to be administered is a human, 0.01 to 100 parts by weight of the concomitant agent may be used with respect to 100 parts by weight of a preparation comprising the active ingredient of the present invention.
Method for Detecting Mutation in RET
[0129] The therapeutic and/or prophylactic agent of the invention of the present application is expected to be therapeutically and/or prophylactically effective by administration to a subject confirmed to have a mutation in RET. This suggests that a patient confirmed to have a mutation in RET is sensitive to the therapeutic and/or prophylactic agent of the invention of the present application. In the present invention, the method for detecting a mutation in RET includes a method for detecting a mutation in RET gene and a method for detecting a mutation in RET protein.
[0130] The method for detecting a mutation in RET gene comprises the step of detecting the presence of a RET gene-related specific polynucleotide shown below in a sample obtained from the subject and the amplification of the specific polynucleotide.
[0131] Specifically, the method comprises the following steps (1) to (3):
(1) A sample (blood, pulmonary alveolus, a biopsied sample, an expectoration sample, etc.) is taken from the subject; (2) Genomic DNA or a transcript thereof (e.g., mRNA, cDNA, protein) is extracted from the sample. The genomic DNA can be extracted by a method known in the art. This extraction can be conveniently performed using a commercially available DNA extraction kit. (3) The presence of a specific polynucleotide in the extracted genomic DNA or transcript thereof (e.g., mRNA, cDNA, protein) and the presence or absence of amplification of the specific polynucleotide are detected.
[0132] The presence of the specific polynucleotide can be detected using gene analysis methods known in the art (e.g., methods such as PCR, reverse transcription PCR, Sanger sequencing, in situ hybridization and microarray method) singly or in combination.
[0133] In the event of detecting the presence of the specific polynucleotide sequence by using mRNA, the detection can be performed by gene amplification reaction such as reverse transcription PCR using primers designed to be capable of specifically amplifying the polynucleotide sequence to be detected. The primer design can be performed using primer design software (e.g., Primer Express; PE Biosystems) or the like.
[0134] In addition, the PCR products which are obtained by PCR and reverse transcription PCR are analyzed by agarose gel electrophoresis, and the successful obtainment of an amplification fragment with a size of interest can be confirmed by ethidium bromide staining or the like. The successful obtainment of an amplification fragment with a size of interest shows that the specific polynucleotide is present in the sample obtained from the subject.
[0135] A point mutation, deletion mutation or insertion mutation in RET gene can be detected by detecting the presence of the specific polynucleotide using, for example, a combined method of the above reverse transcription PCR and Sanger sequencing, or a single-nucleotide extension reaction method known in the art.
[0136] A fusion gene between RET gene and another gene can be detected by a method for detecting the presence of the specific polynucleotide using a combined method of the above reverse transcription PCR and Sanger sequencing or using an in situ hybridization technique. The detection using the in situ hybridization technique can be performed by, for example, fluorescent in situ hybridization (FISH), chromogenic in situ hybridization (CISH) or silver in situ hybridization (SISH) known in the art.
[0137] A probe which can be used in hybridization is a nucleic acid molecule of at least 32 consecutive nucleotides (16 upstream nucleotides and 16 downstream nucleotides flanking the fusion point) that hybridizes under stringent conditions (preferably under more stringent conditions) to the specific polynucleotide or its complementary strand, but not limited to. A probe comprising the sequence of a specific portion in a polynucleotide having a nucleotide sequence selected from the group consisting of SEQ ID NOs: 5 to 14, 25 and 26, or its complementary strand can also be used.
[0138] The stringent conditions can be determined on the basis of the melting temperature (Tm) of a nucleic acid to form a complex according to a routine method. Specifically, the stringent conditions involve "5×SSPE. 5×Denhardt's solution, 0.5% SDS, 50% formamide, 200 μg/ml salmon sperm DNA, 42° C. overnight" as conditions for hybridization and "0.5×SSC, 0.1% SDS, 42° C." as conditions for washing. More stringent conditions involve "5×SSPE, 5×Denhardt's solution, 0.5% SDS, 50% formamide, 200 μg/ml salmon sperm DNA, 42° C. overnight" as conditions for hybridization and "0.2×SSC, 0.1% SDS, 65° C." as conditions for washing.
[0139] Detection of the amplification of RET gene can be conducted by detecting the amplification of the specific polynucleotide by the above in situ hybridization technique or by comparative genomic hybridization (CGH) using genomic DNA.
[0140] The specific polynucleotide to be detected refers to a polynucleotide having a base varied due to a point mutation, deletion mutation or insertion mutation in polynucleotide constituting RET gene, a polynucleotide constituting the fusion gene between RET gene and another gene (e.g., KIF5B gene, CCDC6 gene, NCOA4 gene, TRIM33 gene), or amplified polynucleotide constituting RET gene. Examples of such a polynucleotide include, but are not limited to, the polynucleotides shown below and polynucleotides hybridizing under stringent conditions to polynucleotides consisting of sequences complementary to these polynucleotides (particularly polynucleotides encoding polypeptides having tyrosine kinase activity).
(1) Polynucleotide Constituting Fusion Gene Between RET Gene and KIF5B Gene:
[0141] Polynucleotide comprising the nucleotide sequence shown in SEQ ID NO: 5
[0142] Polynucleotide comprising the nucleotide sequence shown in SEQ ID NO: 6
[0143] Polynucleotide comprising the nucleotide sequence shown in SEQ ID NO: 7
[0144] Polynucleotide comprising the nucleotide sequence shown in SEQ ID NO: 8
[0145] Polynucleotide comprising the nucleotide sequence shown in SEQ ID NO: 9
[0146] Polynucleotide comprising the nucleotide sequence shown in SEQ ID NO: 10
[0147] Polynucleotide comprising the nucleotide sequence shown in SEQ ID NO: 11
[0148] Polynucleotide comprising the nucleotide sequence shown in SEQ ID NO: 12
[0149] Polynucleotide comprising the nucleotide sequence shown in SEQ ID NO: 13
[0150] Polynucleotide comprising the nucleotide sequence shown in SEQ ID NO: 14
(2) Polynucleotide Constituting Fusion Gene Between RET Gene and CCDC6 Gene:
[0151] Polynucleotide comprising the nucleotide sequence shown in SEQ ID NO: 25
[0152] Polynucleotide comprising the nucleotide sequence shown in SEQ ID NO: 26
(3) Polynucleotide Constituting RET Gene:
[0153] Polynucleotide comprising the nucleotide sequence shown in SEQ ID NO: 1
[0154] Polynucleotide comprising the nucleotide sequence shown in SEQ ID NO: 2
(4) Polynucleotide Having a Base Varied Due to a Point Mutation, Deletion Mutation or Insertion Mutation in Polynucleotide Constituting RET Gene:
[0155] Polynucleotide comprising a nucleotide sequence with a mutation in the nucleotide 2091 G, 2261G, 2494G, 2562A, 2600G, 2861 T or 2943T (e.g., 2091G>T, 2261G>A, 2494G>C, 2562A>T, 2600G>A, 2600G>C, 2861T>G or 2943T>C mutation) of a polynucleotide having the nucleotide sequence shown in SEQ ID NO: 1
[0156] Polynucleotide comprising a polynucleotide encoding a polypeptide with a mutation in the amino acid C609, C611, C618, C620, C630, C634, E768, V804, S891, A883 or M918 (e.g., C634W, C634Y, E768D, V804M. V804L or M918T mutation) of a polypeptide having the amino acid sequence shown in SEQ ID NO: 3
[0157] The method for detecting a mutation in RET further includes a method for detecting a mutation in RET protein in addition to the above method.
[0158] The method for detecting a mutation in RET comprises the step of detecting the presence of a specific polypeptide (hereinafter, referred to as a polypeptide to be detected) in a sample obtained from the subject. The step of detecting a polypeptide to be detected involves preparing a lysate from a sample obtained from the subject (e.g., cancer tissues or cells obtained from the subject).
[0159] In the event that a polypeptide to be detected is fusion protein between RET protein and another protein, the presence of polypeptide to be detected can be detected by for example, immunoassay or enzyme activity assay using an antibody against KIF5B, CCDC6, NCOA4 or TRIM33 and an anti-RET antibody in combination. Preferably, an approach such as enzyme immunoassay, two-antibody sandwich ELISA, fluorescent immunoassay, radioimmunoassay or Western blotting using a monoclonal or polyclonal antibody specific for the polypeptide to be detected can be used. In addition to above mentioned method, detection of a mutation (including a point mutation, a deletion mutation and an insertion mutation) in RET protein can be conducted by detecting the presence of a polypeptide to be detected using Western blotting, mass spectrometry, or the like.
[0160] Examples of the polypeptide to be detected include, but are not limited to, the polypeptides shown below and polypeptides with deletion, substitution and/or insertion of one or more amino acids (e.g., 1 to 10, 1 to 5, or 1 to 3 amino acids) in these polypeptides (particularly polypeptides having tyrosine kinase activity).
(1) Polypeptide Constituting Fusion Protein Between RET Protein and KIF5B Protein:
[0161] Polypeptide comprising the amino acid sequence shown in SEQ ID NO: 15
[0162] Polypeptide comprising the amino acid sequence shown in SEQ ID NO: 16
[0163] Polypeptide comprising the amino acid sequence shown in SEQ ID NO: 17
[0164] Polypeptide comprising the amino acid sequence shown in SEQ ID NO: 18
[0165] Polypeptide comprising the amino acid sequence shown in SEQ ID NO: 19
[0166] Polypeptide comprising the amino acid sequence shown in SEQ ID NO: 20
[0167] Polypeptide comprising the amino acid sequence shown in SEQ ID NO: 21
[0168] Polypeptide comprising the amino acid sequence shown in SEQ ID NO: 22
[0169] Polypeptide comprising the amino acid sequence shown in SEQ ID NO: 23
[0170] Polypeptide comprising the amino acid sequence shown in SEQ ID NO: 24
(2) Polypeptide Constituting Fusion Protein Between RET Protein and CCDC6 Protein:
[0171] Polypeptide comprising the amino acid sequence shown in SEQ ID NO: 27
[0172] Polypeptide comprising the amino acid sequence shown in SEQ ID NO: 28
(3) Polypeptide Constituting RET Protein
[0173] Polypeptide comprising the amino acid sequence shown in SEQ ID NO: 3
[0174] Polypeptide comprising the amino acid sequence shown in SEQ ID NO: 4
(4) Polypeptide Having a Point Mutation in a Polypeptide Constituting RET Protein
[0175] Polypeptide encoded by a polynucleotide comprising a nucleotide sequence with a mutation in the nucleotide 2091G, 2261G, 2494G, 2562A, 26000, 2861T or 2943T (e.g., 2091G>T, 2261G>A, 2494G>C, 2562A>T, 2600G>A, 2600G>C, 2861T>G or 2943T>C mutation) of a polynucleotide having the nucleotide sequence shown in SEQ ID NO: 1
[0176] Polypeptide with a mutation in the amino acid C609. C611. C618, C620, C630, C634, G691, E768, Y791, V804, 5891, A883 or M918 (e.g., C634W, C634Y, G691 S, E768D, Y791F, V804M, V804L, S891A or M918T mutation) of a polypeptide having the amino acid sequence shown in SEQ ID NO: 3
[0177] In addition, the presence of the fusion gene between RET gene and KIF5B gene or other fusion genes can be detected by methods described in International Publication No. WO2012/014795, Nature Medicine, 2012, 18, p. 378-381, J Clin Oncol, 30 (35), Dec. 10, 2012, p. 4352-9, Cancer Discov 2013 June, 3 (6), June 2013, p. 630-5, etc.
[0178] In addition to the above method, the activation of RET tyrosine kinase may be dctectcd. The activation of RET tyrosine kinase can be confirmed by detecting phosphorylated RET in a tumor tissue by immunostaining or the like using an anti-phosphorylated RET antibody.
EXAMPLES
[0179] Hereinafter, the present invention will be described more specifically with reference to Examples. However, the present invention is not intended to be limited to these Examples.
[0180] Compound 1 (9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,1-dihy- dro-5H-benzo[b]carbazole-3-carbonitrile, or 9-ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-6,11-dih- ydro-5H-benzo[b]carbazole-3-carbonitrile) represented by formula II (compound described in Example 366 of WO2010/143664) was subjected to pharmacological tests described in Examples 1 to 6.
##STR00006##
Example 1
Evaluation of RET Kinase Inhibitory Activity and Binding Affinity
[0181] The RET kinase inhibitory activity of compound 1 was evaluated with inhibitory activity against the phosphorylation reaction of a biotinylated peptide (EGPWLEEEEEAYGWMDF) as an index using RET kinase containing a N-terminally GST-tagged RET kinase domain (Carna Biosciences). The phosphorylated biotinylated peptide was detected by the TR-FRET (time-resolved fluorescence resonance energy transfer) method using an europium labeled anti-phosphorylation antibody. 50% inhibition concentration (IC50 value) was calculated by the logistic regression method. As a result, compound 1 exhibited RET kinase inhibitory activity with an IC50 value of 4.8 nM.
[0182] The dissociation constant (Kd value) of compound 1 for RET kinase was also measured by KINOMEstSCAN® (DiscoveRx). As a result, compound 1 exhibited binding affinity to RET with Kd value of 7.6 nM.
Example 2
Establishment of KIF5B-RET-Expressing Cells and Evaluation of Cell Growth Inhibitory Activity Against these Cells
[0183] An expression plasmid CS-GS 104J-M67 (GeneCopoeia) containing KIF5B-RET variant 1 (gene in which a region from the N-terminus of KIF5B CDS to exon 15 was fused with a region from exon 12 of RET CDS to the C-terminus) (SEQ ID NO: 5) was transfected into mouse lymphocytes Ba/F3 (RIKEN Cell Bank) by electroporation. After transfection, the cells were cultured overnight in an RPMI-1640 medium (Sigma-Aldrich) containing 10% FBS (Bovogen Biologicals) and 1 ng/mL recombinant mouse IL-3 (R&D systems). Then, the culture supernatant was replaced with an RPMI-1640 medium containing 10% FBS. The cells were seeded into a 96-well plate by the limiting dilution method. Approximately 2 weeks later, the expression of phosphorylated RET in cells grown in the absence of IL-3 was detected by Western blotting. This was used as an index to establish a cell line Ba/F3 KIF5B-RET stably expressing KIF5B-RET.
[0184] The Ba/F3 KIF5BR-RET cells were seeded into a 96-well plate at a concentration of 2,500 cells/well in an RPMI-1640 medium containing 10% FBS. A hydrochloride salt of compound 1 was diluted to 1 nM to 10 μM (final concentrations) with dimethyl sulfoxide and added to the 96-well plate. Dimethyl sulfoxide was added as a negative control. After culture at 37° C. for 2 days in the presence of 5% CO2, a cell counting reagent CellTiter-Glo® Luminescent Cell Viability Assay (Promega Corporation) was added thereto and stirred, followed by the measurement of luminescence intensity using a luminescence measurement apparatus Envision (PerkinElmer). The measurement value in a well supplemented with only a medium was defined as a cell viability of 0%, while the measurement value in a well supplemented with dimethyl sulfoxide was defined as a cell viability of 100%. The cell viability of the Ba/F3 KIF5B-RET cells was calculated at each concentration of compound 1. The IC50 value was determined from the obtained values by the logistic regression method. As a result, compound 1 inhibited cell growth of Ba/F3 KIF5B-RET cells with IC50 value of 86 nM.
[0185] These results demonstrated that compound 1 can inhibit the kinase activity of RET and can inhibit the growth of a cell line expressing KIF5B-RET.
Example 3
Evaluation of Cell Growth Inhibitory Activity Against Thyroid Medullary Cancer Cell Line TT
[0186] Cell growth inhibitory activity was evaluated using a thyroid medullary cancer cell line TT (American Type Culture Collection) with a RET kinase active mutation (C634W). The TT cells were seeded into a 96-well plate at a concentration of 5,000 cells/well in F-12K Nutrient Mixture (Life Technologies Corporation) containing 10% FBS and cultured overnight at 37° C. in the presence of 5% CO2. Then, a hydrochloride salt of compound 1 was diluted to 1 nM to 10 μM (final concentrations) with dimethyl sulfoxide and added to the 96-well plate. Dimethyl sulfoxide was added as a negative control. After culture at 37° C. for 5 days in the presence of 5% CO2, a cell counting reagent CellTiter-Glo® Luminescent Cell Viability Assay was added thereto and stirred, followed by the measurement of luminescence intensity using a luminescence measurement apparatus Envision. The measurement value in a well supplemented with only a medium was defined as a cell viability of 0%, while the measurement value in a well supplemented with dimethyl sulfoxide was defined as a survival rate of 100%. The cell viability of the TT cells was calculated at each concentration of compound 1. The IC50 value was determined from the obtained values by the logistic regression method. As a result, compound 1 inhibited cell growth of TT cells with IC50 value of 190 nM.
Example 4
REF Kinase Mutant Inhibitory Activity
[0187] The RET kinase mutant inhibitory activity of compound 1 was evaluated with inhibitory activity against the phosphorylation reaction of a biotinylated peptide (EGPWLEEEEEAYGWMDF) as an index using a RET kinase mutant containing a N-terminally GST-tagged RET kinase domain (Carna Biosciences, Millipore). The phosphorylated biotinylated peptide was detected by the TR-FRET method using an europium labeled anti-phosphorylation antibody. The IC50 value was calculated by the logistic regression method. The test results are shown in Table 1. Compound 1 exhibited inhibitory activity against each mutant of RET kinase with a mutation (V804L, V804M) in a gatekeeper residue.
TABLE-US-00001 TABLE 1 RET mutant IC50 (nM) RET G691S 9.5 RET Y791F 14 RET V804L 32 RET V804M 53 RET S891A 8.3 RET M918T 5.7
Example 5
Evaluation of Cell Growth Inhibitory Activity Against Non-Small Cell Lung Cancer Cell Line LC-2/ad
[0188] Cell growth inhibitory activity was evaluated using a non-small cell lung cancer cell line LC-2/ad (RIKEN, J Thorac Oncol. 2012 December, 7 (12), 1872-6) harboring CCDC6-RET fusion gene.
[0189] The LC-2/ad cells were seeded into a 96-well plate at a concentration of 2,000 cells/well in a medium of a 1:1 mixture of RPMI-1640 and Ham containing 15% FBS and 25 mM HEPES and cultured overnight at 37° C. in the presence of 5% CO2. Then, a hydrochloride salt of compound 1 was diluted to 1 nM to 1 μM (final concentrations) with dimethyl sulfoxide and added to the 96-well plate. Dimethyl sulfoxide was added as a negative control. After culture at 37° C. for 5 days in the presence of 5% CO2, a cell counting reagent CellTiter-Glo® Luminescent Cell Viability Assay was added thereto and stirred, followed by the measurement of luminescence intensity using a luminescence measurement apparatus Envision. The measurement value in a well supplemented with only a medium was defined as a cell viability of 0%, while the measurement value in a well supplemented with dimethyl sulfoxide was defined as a cell viability of 100%. The cell viability of the LC-2/ad cells was calculated at each concentration of compound 1. The IC50 value was determined from the obtained values by the logistic regression method. As a result, compound 1 inhibited cell growth of LC-2/ad cells with IC50 value of 190 nM.
Example 6
Evaluation of Antitumor Activity in Xenograft Mouse Model Harboring CCDC6-RET Fusion Gene
[0190] The in vivo antitumor activity of compound 1 was evaluated in non-small cell lung cancer cell line LC-2/ad-implanted mouse models. LC-2/ad was subcutaneously implanted to SCID mice and randomized after tumor size reached 200 to 350 mm. The administration of the compound was started on the day of randamization. The vehicles used for dissolving the compound were 0.02 N HCl, 10% dimethyl sulfoxide. 10% Cremophor EL, 15% PEG400 and 15% HPCD (2-hydroxypropyl-ji-cyclodextrin) (indicated by final concentration). Compound 1 was orally administered once a day to each mouse at a dose of 20 mg/kg or 60 mg/kg for 14 days. As a result, a dose-dependent tumor growth inhibitory effect and tumor regression were confirmed for all tumors. During this test, a significant body weight loss of a mouse was not observed at any dose. The results about the antitumor activity are shown in FIG. 1.
Sequence CWU
1
1
4614174DNAHomo sapiensmisc_featureRET transcript variant 4 (NM_020630.4 )
1agtcccgcga ccgaagcagg gcgcgcagca gcgctgagtg ccccggaacg tgcgtcgcgc
60ccccagtgtc cgtcgcgtcc gccgcgcccc gggcggggat ggggcggcca gactgagcgc
120cgcacccgcc atccagaccc gccggcccta gccgcagtcc ctccagccgt ggccccagcg
180cgcacgggcg atggcgaagg cgacgtccgg tgccgcgggg ctgcgtctgc tgttgctgct
240gctgctgccg ctgctaggca aagtggcatt gggcctctac ttctcgaggg atgcttactg
300ggagaagctg tatgtggacc aggcggccgg cacgcccttg ctgtacgtcc atgccctgcg
360ggacgcccct gaggaggtgc ccagcttccg cctgggccag catctctacg gcacgtaccg
420cacacggctg catgagaaca actggatctg catccaggag gacaccggcc tcctctacct
480taaccggagc ctggaccata gctcctggga gaagctcagt gtccgcaacc gcggctttcc
540cctgctcacc gtctacctca aggtcttcct gtcacccaca tcccttcgtg agggcgagtg
600ccagtggcca ggctgtgccc gcgtatactt ctccttcttc aacacctcct ttccagcctg
660cagctccctc aagccccggg agctctgctt cccagagaca aggccctcct tccgcattcg
720ggagaaccga cccccaggca ccttccacca gttccgcctg ctgcctgtgc agttcttgtg
780ccccaacatc agcgtggcct acaggctcct ggagggtgag ggtctgccct tccgctgcgc
840cccggacagc ctggaggtga gcacgcgctg ggccctggac cgcgagcagc gggagaagta
900cgagctggtg gccgtgtgca ccgtgcacgc cggcgcgcgc gaggaggtgg tgatggtgcc
960cttcccggtg accgtgtacg acgaggacga ctcggcgccc accttccccg cgggcgtcga
1020caccgccagc gccgtggtgg agttcaagcg gaaggaggac accgtggtgg ccacgctgcg
1080tgtcttcgat gcagacgtgg tacctgcatc aggggagctg gtgaggcggt acacaagcac
1140gctgctcccc ggggacacct gggcccagca gaccttccgg gtggaacact ggcccaacga
1200gacctcggtc caggccaacg gcagcttcgt gcgggcgacc gtacatgact ataggctggt
1260tctcaaccgg aacctctcca tctcggagaa ccgcaccatg cagctggcgg tgctggtcaa
1320tgactcagac ttccagggcc caggagcggg cgtcctcttg ctccacttca acgtgtcggt
1380gctgccggtc agcctgcacc tgcccagtac ctactccctc tccgtgagca ggagggctcg
1440ccgatttgcc cagatcggga aagtctgtgt ggaaaactgc caggcattca gtggcatcaa
1500cgtccagtac aagctgcatt cctctggtgc caactgcagc acgctagggg tggtcacctc
1560agccgaggac acctcgggga tcctgtttgt gaatgacacc aaggccctgc ggcggcccaa
1620gtgtgccgaa cttcactaca tggtggtggc caccgaccag cagacctcta ggcaggccca
1680ggcccagctg cttgtaacag tggaggggtc atatgtggcc gaggaggcgg gctgccccct
1740gtcctgtgca gtcagcaaga gacggctgga gtgtgaggag tgtggcggcc tgggctcccc
1800aacaggcagg tgtgagtgga ggcaaggaga tggcaaaggg atcaccagga acttctccac
1860ctgctctccc agcaccaaga cctgccccga cggccactgc gatgttgtgg agacccaaga
1920catcaacatt tgccctcagg actgcctccg gggcagcatt gttgggggac acgagcctgg
1980ggagccccgg gggattaaag ctggctatgg cacctgcaac tgcttccctg aggaggagaa
2040gtgcttctgc gagcccgaag acatccagga tccactgtgc gacgagctgt gccgcacggt
2100gatcgcagcc gctgtcctct tctccttcat cgtctcggtg ctgctgtctg ccttctgcat
2160ccactgctac cacaagtttg cccacaagcc acccatctcc tcagctgaga tgaccttccg
2220gaggcccgcc caggccttcc cggtcagcta ctcctcttcc ggtgcccgcc ggccctcgct
2280ggactccatg gagaaccagg tctccgtgga tgccttcaag atcctggagg atccaaagtg
2340ggaattccct cggaagaact tggttcttgg aaaaactcta ggagaaggcg aatttggaaa
2400agtggtcaag gcaacggcct tccatctgaa aggcagagca gggtacacca cggtggccgt
2460gaagatgctg aaagagaacg cctccccgag tgagcttcga gacctgctgt cagagttcaa
2520cgtcctgaag caggtcaacc acccacatgt catcaaattg tatggggcct gcagccagga
2580tggcccgctc ctcctcatcg tggagtacgc caaatacggc tccctgcggg gcttcctccg
2640cgagagccgc aaagtggggc ctggctacct gggcagtgga ggcagccgca actccagctc
2700cctggaccac ccggatgagc gggccctcac catgggcgac ctcatctcat ttgcctggca
2760gatctcacag gggatgcagt atctggccga gatgaagctc gttcatcggg acttggcagc
2820cagaaacatc ctggtagctg aggggcggaa gatgaagatt tcggatttcg gcttgtcccg
2880agatgtttat gaagaggatt cctacgtgaa gaggagccag ggtcggattc cagttaaatg
2940gatggcaatt gaatcccttt ttgatcatat ctacaccacg caaagtgatg tatggtcttt
3000tggtgtcctg ctgtgggaga tcgtgaccct agggggaaac ccctatcctg ggattcctcc
3060tgagcggctc ttcaaccttc tgaagaccgg ccaccggatg gagaggccag acaactgcag
3120cgaggagatg taccgcctga tgctgcaatg ctggaagcag gagccggaca aaaggccggt
3180gtttgcggac atcagcaaag acctggagaa gatgatggtt aagaggagag actacttgga
3240ccttgcggcg tccactccat ctgactccct gatttatgac gacggcctct cagaggagga
3300gacaccgctg gtggactgta ataatgcccc cctccctcga gccctccctt ccacatggat
3360tgaaaacaaa ctctatggta gaatttccca tgcatttact agattctagc accgctgtcc
3420cctctgcact atccttcctc tctgtgatgc tttttaaaaa tgtttctggt ctgaacaaaa
3480ccaaagtctg ctctgaacct ttttatttgt aaatgtctga ctttgcatcc agtttacatt
3540taggcattat tgcaactatg tttttctaaa aggaagtgaa aataagtgta attaccacat
3600tgcccagcaa cttaggatgg tagaggaaaa aacagatcag ggcggaactc tcaggggaga
3660ccaagaacag gttgaataag gcgcttctgg ggtgggaatc aagtcatagt acttctactt
3720taactaagtg gataaatata caaatctggg gaggtattca gttgagaaag gagccaccag
3780caccactcag cctgcactgg gagcacagcc aggttccccc agacccctcc tgggcaggca
3840ggtgcctctc agaggccacc cggcactggc gagcagccac tggccaagcc tcagccccag
3900tcccagccac atgtcctcca tcaggggtag cgaggttgca ggagctggct ggccctggga
3960ggacgcaccc ccactgctgt tttcacatcc tttcccttac ccaccttcag gacggttgtc
4020acttatgaag tcagtgctaa agctggagca gttgcttttt gaaagaacat ggtctgtggt
4080gctgtggtct tacaatggac agtaaatatg gttcttgcca aaactccttc ttttgtcttt
4140gattaaatac tagaaattta aaaaaaaaaa aaaa
417425629DNAHomo sapiensmisc_featureRET transcript variant 2
(NM_020975.4) 2agtcccgcga ccgaagcagg gcgcgcagca gcgctgagtg ccccggaacg
tgcgtcgcgc 60ccccagtgtc cgtcgcgtcc gccgcgcccc gggcggggat ggggcggcca
gactgagcgc 120cgcacccgcc atccagaccc gccggcccta gccgcagtcc ctccagccgt
ggccccagcg 180cgcacgggcg atggcgaagg cgacgtccgg tgccgcgggg ctgcgtctgc
tgttgctgct 240gctgctgccg ctgctaggca aagtggcatt gggcctctac ttctcgaggg
atgcttactg 300ggagaagctg tatgtggacc aggcggccgg cacgcccttg ctgtacgtcc
atgccctgcg 360ggacgcccct gaggaggtgc ccagcttccg cctgggccag catctctacg
gcacgtaccg 420cacacggctg catgagaaca actggatctg catccaggag gacaccggcc
tcctctacct 480taaccggagc ctggaccata gctcctggga gaagctcagt gtccgcaacc
gcggctttcc 540cctgctcacc gtctacctca aggtcttcct gtcacccaca tcccttcgtg
agggcgagtg 600ccagtggcca ggctgtgccc gcgtatactt ctccttcttc aacacctcct
ttccagcctg 660cagctccctc aagccccggg agctctgctt cccagagaca aggccctcct
tccgcattcg 720ggagaaccga cccccaggca ccttccacca gttccgcctg ctgcctgtgc
agttcttgtg 780ccccaacatc agcgtggcct acaggctcct ggagggtgag ggtctgccct
tccgctgcgc 840cccggacagc ctggaggtga gcacgcgctg ggccctggac cgcgagcagc
gggagaagta 900cgagctggtg gccgtgtgca ccgtgcacgc cggcgcgcgc gaggaggtgg
tgatggtgcc 960cttcccggtg accgtgtacg acgaggacga ctcggcgccc accttccccg
cgggcgtcga 1020caccgccagc gccgtggtgg agttcaagcg gaaggaggac accgtggtgg
ccacgctgcg 1080tgtcttcgat gcagacgtgg tacctgcatc aggggagctg gtgaggcggt
acacaagcac 1140gctgctcccc ggggacacct gggcccagca gaccttccgg gtggaacact
ggcccaacga 1200gacctcggtc caggccaacg gcagcttcgt gcgggcgacc gtacatgact
ataggctggt 1260tctcaaccgg aacctctcca tctcggagaa ccgcaccatg cagctggcgg
tgctggtcaa 1320tgactcagac ttccagggcc caggagcggg cgtcctcttg ctccacttca
acgtgtcggt 1380gctgccggtc agcctgcacc tgcccagtac ctactccctc tccgtgagca
ggagggctcg 1440ccgatttgcc cagatcggga aagtctgtgt ggaaaactgc caggcattca
gtggcatcaa 1500cgtccagtac aagctgcatt cctctggtgc caactgcagc acgctagggg
tggtcacctc 1560agccgaggac acctcgggga tcctgtttgt gaatgacacc aaggccctgc
ggcggcccaa 1620gtgtgccgaa cttcactaca tggtggtggc caccgaccag cagacctcta
ggcaggccca 1680ggcccagctg cttgtaacag tggaggggtc atatgtggcc gaggaggcgg
gctgccccct 1740gtcctgtgca gtcagcaaga gacggctgga gtgtgaggag tgtggcggcc
tgggctcccc 1800aacaggcagg tgtgagtgga ggcaaggaga tggcaaaggg atcaccagga
acttctccac 1860ctgctctccc agcaccaaga cctgccccga cggccactgc gatgttgtgg
agacccaaga 1920catcaacatt tgccctcagg actgcctccg gggcagcatt gttgggggac
acgagcctgg 1980ggagccccgg gggattaaag ctggctatgg cacctgcaac tgcttccctg
aggaggagaa 2040gtgcttctgc gagcccgaag acatccagga tccactgtgc gacgagctgt
gccgcacggt 2100gatcgcagcc gctgtcctct tctccttcat cgtctcggtg ctgctgtctg
ccttctgcat 2160ccactgctac cacaagtttg cccacaagcc acccatctcc tcagctgaga
tgaccttccg 2220gaggcccgcc caggccttcc cggtcagcta ctcctcttcc ggtgcccgcc
ggccctcgct 2280ggactccatg gagaaccagg tctccgtgga tgccttcaag atcctggagg
atccaaagtg 2340ggaattccct cggaagaact tggttcttgg aaaaactcta ggagaaggcg
aatttggaaa 2400agtggtcaag gcaacggcct tccatctgaa aggcagagca gggtacacca
cggtggccgt 2460gaagatgctg aaagagaacg cctccccgag tgagcttcga gacctgctgt
cagagttcaa 2520cgtcctgaag caggtcaacc acccacatgt catcaaattg tatggggcct
gcagccagga 2580tggcccgctc ctcctcatcg tggagtacgc caaatacggc tccctgcggg
gcttcctccg 2640cgagagccgc aaagtggggc ctggctacct gggcagtgga ggcagccgca
actccagctc 2700cctggaccac ccggatgagc gggccctcac catgggcgac ctcatctcat
ttgcctggca 2760gatctcacag gggatgcagt atctggccga gatgaagctc gttcatcggg
acttggcagc 2820cagaaacatc ctggtagctg aggggcggaa gatgaagatt tcggatttcg
gcttgtcccg 2880agatgtttat gaagaggatt cctacgtgaa gaggagccag ggtcggattc
cagttaaatg 2940gatggcaatt gaatcccttt ttgatcatat ctacaccacg caaagtgatg
tatggtcttt 3000tggtgtcctg ctgtgggaga tcgtgaccct agggggaaac ccctatcctg
ggattcctcc 3060tgagcggctc ttcaaccttc tgaagaccgg ccaccggatg gagaggccag
acaactgcag 3120cgaggagatg taccgcctga tgctgcaatg ctggaagcag gagccggaca
aaaggccggt 3180gtttgcggac atcagcaaag acctggagaa gatgatggtt aagaggagag
actacttgga 3240ccttgcggcg tccactccat ctgactccct gatttatgac gacggcctct
cagaggagga 3300gacaccgctg gtggactgta ataatgcccc cctccctcga gccctccctt
ccacatggat 3360tgaaaacaaa ctctatggca tgtcagaccc gaactggcct ggagagagtc
ctgtaccact 3420cacgagagct gatggcacta acactgggtt tccaagatat ccaaatgata
gtgtatatgc 3480taactggatg ctttcaccct cagcggcaaa attaatggac acgtttgata
gttaacattt 3540ctttgtgaaa ggtaatggac tcacaagggg aagaaacatg ctgagaatgg
aaagtctacc 3600ggccctttct ttgtgaacgt cacattggcc gagccgtgtt cagttcccag
gtggcagact 3660cgtttttggt agtttgtttt aacttccaag gtggttttac ttctgatagc
cggtgatttt 3720ccctcctagc agacatgcca caccgggtaa gagctctgag tcttagtggt
taagcattcc 3780tttctcttca gtgcccagca gcacccagtg ttggtctgtg tccatcagtg
accaccaaca 3840ttctgtgttc acatgtgtgg gtccaacact tactacctgg tgtatgaaat
tggacctgaa 3900ctgttggatt tttctagttg ccgccaaaca aggcaaaaaa atttaaacat
gaagcacaca 3960cacaaaaaag gcagtaggaa aaatgctggc cctgatgacc tgtccttatt
cagaatgaga 4020gactgcgggg ggggcctggg ggtagtgtca atgcccctcc agggctggag
gggaagaggg 4080gccccgagga tgggcctggg ctcagcattc gagatcttga gaatgatttt
tttttaatca 4140tgcaaccttt ccttaggaag acatttggtt ttcatcatga ttaagatgat
tcctagattt 4200agcacaatgg agagattcca tgccatcttt actatgtgga tggtggtatc
agggaagagg 4260gctcacaaga cacatttgtc ccccgggccc accacatcat cctcacgtgt
tcggtactga 4320gcagccacta cccctgatga gaacagtatg aagaaagggg gctgttggag
tcccagaatt 4380gctgacagca gaggctttgc tgctgtgaat cccacctgcc accagcctgc
agcacacccc 4440acagccaagt agaggcgaaa gcagtggctc atcctacctg ttaggagcag
gtagggcttg 4500tactcacttt aatttgaatc ttatcaactt actcataaag ggacaggcta
gctagctgtg 4560ttagaagtag caatgacaat gaccaaggac tgctacacct ctgattacaa
ttctgatgtg 4620aaaaagatgg tgtttggctc ttatagagcc tgtgtgaaag gcccatggat
cagctcttcc 4680tgtgtttgta atttaatgct gctacaagat gtttctgttt cttagattct
gaccatgact 4740cataagcttc ttgtcattct tcattgcttg tttgtggtca cagatgcaca
acactcctcc 4800agtcttgtgg gggcagcttt tgggaagtct cagcagctct tctggctgtg
ttgtcagcac 4860tgtaacttcg cagaaaagag tcggattacc aaaacactgc ctgctcttca
gacttaaagc 4920actgatagga cttaaaatag tctcattcaa atactgtatt ttatataggc
atttcacaaa 4980aacagcaaaa ttgtggcatt ttgtgaggcc aaggcttgga tgcgtgtgta
atagagcctt 5040gtggtgtgtg cgcacacacc cagagggaga gtttgaaaaa tgcttattgg
acacgtaacc 5100tggctctaat ttgggctgtt tttcagatac actgtgataa gttcttttac
aaatatctat 5160agacatggta aacttttggt tttcagatat gcttaatgat agtcttacta
aatgcagaaa 5220taagaataaa ctttctcaaa ttattaaaaa tgcctacaca gtaagtgtga
attgctgcaa 5280caggtttgtt ctcaggaggg taagaactcc aggtctaaac agctgaccca
gtgatgggga 5340atttatcctt gaccaattta tccttgacca ataacctaat tgtctattcc
tgagttataa 5400aagtccccat ccttattagc tctactggaa ttttcataca cgtaaatgca
gaagttacta 5460agtattaagt attactgagt attaagtagt aatctgtcag ttattaaaat
ttgtaaaatc 5520tatttatgaa aggtcattaa accagatcat gttccttttt ttgtaatcaa
ggtgactaag 5580aaaatcagtt gtgtaaataa aatcatgtat cataaaaaaa aaaaaaaaa
562931072PRTHomo sapiensMISC_FEATURERET isoform c precursor
(NP_065681.1) 3Met Ala Lys Ala Thr Ser Gly Ala Ala Gly Leu Arg Leu Leu
Leu Leu 1 5 10 15
Leu Leu Leu Pro Leu Leu Gly Lys Val Ala Leu Gly Leu Tyr Phe Ser
20 25 30 Arg Asp Ala Tyr Trp
Glu Lys Leu Tyr Val Asp Gln Ala Ala Gly Thr 35
40 45 Pro Leu Leu Tyr Val His Ala Leu Arg
Asp Ala Pro Glu Glu Val Pro 50 55
60 Ser Phe Arg Leu Gly Gln His Leu Tyr Gly Thr Tyr Arg
Thr Arg Leu 65 70 75
80 His Glu Asn Asn Trp Ile Cys Ile Gln Glu Asp Thr Gly Leu Leu Tyr
85 90 95 Leu Asn Arg Ser
Leu Asp His Ser Ser Trp Glu Lys Leu Ser Val Arg 100
105 110 Asn Arg Gly Phe Pro Leu Leu Thr Val
Tyr Leu Lys Val Phe Leu Ser 115 120
125 Pro Thr Ser Leu Arg Glu Gly Glu Cys Gln Trp Pro Gly Cys
Ala Arg 130 135 140
Val Tyr Phe Ser Phe Phe Asn Thr Ser Phe Pro Ala Cys Ser Ser Leu 145
150 155 160 Lys Pro Arg Glu Leu
Cys Phe Pro Glu Thr Arg Pro Ser Phe Arg Ile 165
170 175 Arg Glu Asn Arg Pro Pro Gly Thr Phe His
Gln Phe Arg Leu Leu Pro 180 185
190 Val Gln Phe Leu Cys Pro Asn Ile Ser Val Ala Tyr Arg Leu Leu
Glu 195 200 205 Gly
Glu Gly Leu Pro Phe Arg Cys Ala Pro Asp Ser Leu Glu Val Ser 210
215 220 Thr Arg Trp Ala Leu Asp
Arg Glu Gln Arg Glu Lys Tyr Glu Leu Val 225 230
235 240 Ala Val Cys Thr Val His Ala Gly Ala Arg Glu
Glu Val Val Met Val 245 250
255 Pro Phe Pro Val Thr Val Tyr Asp Glu Asp Asp Ser Ala Pro Thr Phe
260 265 270 Pro Ala
Gly Val Asp Thr Ala Ser Ala Val Val Glu Phe Lys Arg Lys 275
280 285 Glu Asp Thr Val Val Ala Thr
Leu Arg Val Phe Asp Ala Asp Val Val 290 295
300 Pro Ala Ser Gly Glu Leu Val Arg Arg Tyr Thr Ser
Thr Leu Leu Pro 305 310 315
320 Gly Asp Thr Trp Ala Gln Gln Thr Phe Arg Val Glu His Trp Pro Asn
325 330 335 Glu Thr Ser
Val Gln Ala Asn Gly Ser Phe Val Arg Ala Thr Val His 340
345 350 Asp Tyr Arg Leu Val Leu Asn Arg
Asn Leu Ser Ile Ser Glu Asn Arg 355 360
365 Thr Met Gln Leu Ala Val Leu Val Asn Asp Ser Asp Phe
Gln Gly Pro 370 375 380
Gly Ala Gly Val Leu Leu Leu His Phe Asn Val Ser Val Leu Pro Val 385
390 395 400 Ser Leu His Leu
Pro Ser Thr Tyr Ser Leu Ser Val Ser Arg Arg Ala 405
410 415 Arg Arg Phe Ala Gln Ile Gly Lys Val
Cys Val Glu Asn Cys Gln Ala 420 425
430 Phe Ser Gly Ile Asn Val Gln Tyr Lys Leu His Ser Ser Gly
Ala Asn 435 440 445
Cys Ser Thr Leu Gly Val Val Thr Ser Ala Glu Asp Thr Ser Gly Ile 450
455 460 Leu Phe Val Asn Asp
Thr Lys Ala Leu Arg Arg Pro Lys Cys Ala Glu 465 470
475 480 Leu His Tyr Met Val Val Ala Thr Asp Gln
Gln Thr Ser Arg Gln Ala 485 490
495 Gln Ala Gln Leu Leu Val Thr Val Glu Gly Ser Tyr Val Ala Glu
Glu 500 505 510 Ala
Gly Cys Pro Leu Ser Cys Ala Val Ser Lys Arg Arg Leu Glu Cys 515
520 525 Glu Glu Cys Gly Gly Leu
Gly Ser Pro Thr Gly Arg Cys Glu Trp Arg 530 535
540 Gln Gly Asp Gly Lys Gly Ile Thr Arg Asn Phe
Ser Thr Cys Ser Pro 545 550 555
560 Ser Thr Lys Thr Cys Pro Asp Gly His Cys Asp Val Val Glu Thr Gln
565 570 575 Asp Ile
Asn Ile Cys Pro Gln Asp Cys Leu Arg Gly Ser Ile Val Gly 580
585 590 Gly His Glu Pro Gly Glu Pro
Arg Gly Ile Lys Ala Gly Tyr Gly Thr 595 600
605 Cys Asn Cys Phe Pro Glu Glu Glu Lys Cys Phe Cys
Glu Pro Glu Asp 610 615 620
Ile Gln Asp Pro Leu Cys Asp Glu Leu Cys Arg Thr Val Ile Ala Ala 625
630 635 640 Ala Val Leu
Phe Ser Phe Ile Val Ser Val Leu Leu Ser Ala Phe Cys 645
650 655 Ile His Cys Tyr His Lys Phe Ala
His Lys Pro Pro Ile Ser Ser Ala 660 665
670 Glu Met Thr Phe Arg Arg Pro Ala Gln Ala Phe Pro Val
Ser Tyr Ser 675 680 685
Ser Ser Gly Ala Arg Arg Pro Ser Leu Asp Ser Met Glu Asn Gln Val 690
695 700 Ser Val Asp Ala
Phe Lys Ile Leu Glu Asp Pro Lys Trp Glu Phe Pro 705 710
715 720 Arg Lys Asn Leu Val Leu Gly Lys Thr
Leu Gly Glu Gly Glu Phe Gly 725 730
735 Lys Val Val Lys Ala Thr Ala Phe His Leu Lys Gly Arg Ala
Gly Tyr 740 745 750
Thr Thr Val Ala Val Lys Met Leu Lys Glu Asn Ala Ser Pro Ser Glu
755 760 765 Leu Arg Asp Leu
Leu Ser Glu Phe Asn Val Leu Lys Gln Val Asn His 770
775 780 Pro His Val Ile Lys Leu Tyr Gly
Ala Cys Ser Gln Asp Gly Pro Leu 785 790
795 800 Leu Leu Ile Val Glu Tyr Ala Lys Tyr Gly Ser Leu
Arg Gly Phe Leu 805 810
815 Arg Glu Ser Arg Lys Val Gly Pro Gly Tyr Leu Gly Ser Gly Gly Ser
820 825 830 Arg Asn Ser
Ser Ser Leu Asp His Pro Asp Glu Arg Ala Leu Thr Met 835
840 845 Gly Asp Leu Ile Ser Phe Ala Trp
Gln Ile Ser Gln Gly Met Gln Tyr 850 855
860 Leu Ala Glu Met Lys Leu Val His Arg Asp Leu Ala Ala
Arg Asn Ile 865 870 875
880 Leu Val Ala Glu Gly Arg Lys Met Lys Ile Ser Asp Phe Gly Leu Ser
885 890 895 Arg Asp Val Tyr
Glu Glu Asp Ser Tyr Val Lys Arg Ser Gln Gly Arg 900
905 910 Ile Pro Val Lys Trp Met Ala Ile Glu
Ser Leu Phe Asp His Ile Tyr 915 920
925 Thr Thr Gln Ser Asp Val Trp Ser Phe Gly Val Leu Leu Trp
Glu Ile 930 935 940
Val Thr Leu Gly Gly Asn Pro Tyr Pro Gly Ile Pro Pro Glu Arg Leu 945
950 955 960 Phe Asn Leu Leu Lys
Thr Gly His Arg Met Glu Arg Pro Asp Asn Cys 965
970 975 Ser Glu Glu Met Tyr Arg Leu Met Leu Gln
Cys Trp Lys Gln Glu Pro 980 985
990 Asp Lys Arg Pro Val Phe Ala Asp Ile Ser Lys Asp Leu Glu
Lys Met 995 1000 1005
Met Val Lys Arg Arg Asp Tyr Leu Asp Leu Ala Ala Ser Thr Pro 1010
1015 1020 Ser Asp Ser Leu Ile
Tyr Asp Asp Gly Leu Ser Glu Glu Glu Thr 1025 1030
1035 Pro Leu Val Asp Cys Asn Asn Ala Pro Leu
Pro Arg Ala Leu Pro 1040 1045 1050
Ser Thr Trp Ile Glu Asn Lys Leu Tyr Gly Arg Ile Ser His Ala
1055 1060 1065 Phe Thr
Arg Phe 1070 41114PRTHomo sapiensMISC_FEATURERET isoform a
precursor (NP_066124.1) 4Met Ala Lys Ala Thr Ser Gly Ala Ala Gly Leu Arg
Leu Leu Leu Leu 1 5 10
15 Leu Leu Leu Pro Leu Leu Gly Lys Val Ala Leu Gly Leu Tyr Phe Ser
20 25 30 Arg Asp Ala
Tyr Trp Glu Lys Leu Tyr Val Asp Gln Ala Ala Gly Thr 35
40 45 Pro Leu Leu Tyr Val His Ala Leu
Arg Asp Ala Pro Glu Glu Val Pro 50 55
60 Ser Phe Arg Leu Gly Gln His Leu Tyr Gly Thr Tyr Arg
Thr Arg Leu 65 70 75
80 His Glu Asn Asn Trp Ile Cys Ile Gln Glu Asp Thr Gly Leu Leu Tyr
85 90 95 Leu Asn Arg Ser
Leu Asp His Ser Ser Trp Glu Lys Leu Ser Val Arg 100
105 110 Asn Arg Gly Phe Pro Leu Leu Thr Val
Tyr Leu Lys Val Phe Leu Ser 115 120
125 Pro Thr Ser Leu Arg Glu Gly Glu Cys Gln Trp Pro Gly Cys
Ala Arg 130 135 140
Val Tyr Phe Ser Phe Phe Asn Thr Ser Phe Pro Ala Cys Ser Ser Leu 145
150 155 160 Lys Pro Arg Glu Leu
Cys Phe Pro Glu Thr Arg Pro Ser Phe Arg Ile 165
170 175 Arg Glu Asn Arg Pro Pro Gly Thr Phe His
Gln Phe Arg Leu Leu Pro 180 185
190 Val Gln Phe Leu Cys Pro Asn Ile Ser Val Ala Tyr Arg Leu Leu
Glu 195 200 205 Gly
Glu Gly Leu Pro Phe Arg Cys Ala Pro Asp Ser Leu Glu Val Ser 210
215 220 Thr Arg Trp Ala Leu Asp
Arg Glu Gln Arg Glu Lys Tyr Glu Leu Val 225 230
235 240 Ala Val Cys Thr Val His Ala Gly Ala Arg Glu
Glu Val Val Met Val 245 250
255 Pro Phe Pro Val Thr Val Tyr Asp Glu Asp Asp Ser Ala Pro Thr Phe
260 265 270 Pro Ala
Gly Val Asp Thr Ala Ser Ala Val Val Glu Phe Lys Arg Lys 275
280 285 Glu Asp Thr Val Val Ala Thr
Leu Arg Val Phe Asp Ala Asp Val Val 290 295
300 Pro Ala Ser Gly Glu Leu Val Arg Arg Tyr Thr Ser
Thr Leu Leu Pro 305 310 315
320 Gly Asp Thr Trp Ala Gln Gln Thr Phe Arg Val Glu His Trp Pro Asn
325 330 335 Glu Thr Ser
Val Gln Ala Asn Gly Ser Phe Val Arg Ala Thr Val His 340
345 350 Asp Tyr Arg Leu Val Leu Asn Arg
Asn Leu Ser Ile Ser Glu Asn Arg 355 360
365 Thr Met Gln Leu Ala Val Leu Val Asn Asp Ser Asp Phe
Gln Gly Pro 370 375 380
Gly Ala Gly Val Leu Leu Leu His Phe Asn Val Ser Val Leu Pro Val 385
390 395 400 Ser Leu His Leu
Pro Ser Thr Tyr Ser Leu Ser Val Ser Arg Arg Ala 405
410 415 Arg Arg Phe Ala Gln Ile Gly Lys Val
Cys Val Glu Asn Cys Gln Ala 420 425
430 Phe Ser Gly Ile Asn Val Gln Tyr Lys Leu His Ser Ser Gly
Ala Asn 435 440 445
Cys Ser Thr Leu Gly Val Val Thr Ser Ala Glu Asp Thr Ser Gly Ile 450
455 460 Leu Phe Val Asn Asp
Thr Lys Ala Leu Arg Arg Pro Lys Cys Ala Glu 465 470
475 480 Leu His Tyr Met Val Val Ala Thr Asp Gln
Gln Thr Ser Arg Gln Ala 485 490
495 Gln Ala Gln Leu Leu Val Thr Val Glu Gly Ser Tyr Val Ala Glu
Glu 500 505 510 Ala
Gly Cys Pro Leu Ser Cys Ala Val Ser Lys Arg Arg Leu Glu Cys 515
520 525 Glu Glu Cys Gly Gly Leu
Gly Ser Pro Thr Gly Arg Cys Glu Trp Arg 530 535
540 Gln Gly Asp Gly Lys Gly Ile Thr Arg Asn Phe
Ser Thr Cys Ser Pro 545 550 555
560 Ser Thr Lys Thr Cys Pro Asp Gly His Cys Asp Val Val Glu Thr Gln
565 570 575 Asp Ile
Asn Ile Cys Pro Gln Asp Cys Leu Arg Gly Ser Ile Val Gly 580
585 590 Gly His Glu Pro Gly Glu Pro
Arg Gly Ile Lys Ala Gly Tyr Gly Thr 595 600
605 Cys Asn Cys Phe Pro Glu Glu Glu Lys Cys Phe Cys
Glu Pro Glu Asp 610 615 620
Ile Gln Asp Pro Leu Cys Asp Glu Leu Cys Arg Thr Val Ile Ala Ala 625
630 635 640 Ala Val Leu
Phe Ser Phe Ile Val Ser Val Leu Leu Ser Ala Phe Cys 645
650 655 Ile His Cys Tyr His Lys Phe Ala
His Lys Pro Pro Ile Ser Ser Ala 660 665
670 Glu Met Thr Phe Arg Arg Pro Ala Gln Ala Phe Pro Val
Ser Tyr Ser 675 680 685
Ser Ser Gly Ala Arg Arg Pro Ser Leu Asp Ser Met Glu Asn Gln Val 690
695 700 Ser Val Asp Ala
Phe Lys Ile Leu Glu Asp Pro Lys Trp Glu Phe Pro 705 710
715 720 Arg Lys Asn Leu Val Leu Gly Lys Thr
Leu Gly Glu Gly Glu Phe Gly 725 730
735 Lys Val Val Lys Ala Thr Ala Phe His Leu Lys Gly Arg Ala
Gly Tyr 740 745 750
Thr Thr Val Ala Val Lys Met Leu Lys Glu Asn Ala Ser Pro Ser Glu
755 760 765 Leu Arg Asp Leu
Leu Ser Glu Phe Asn Val Leu Lys Gln Val Asn His 770
775 780 Pro His Val Ile Lys Leu Tyr Gly
Ala Cys Ser Gln Asp Gly Pro Leu 785 790
795 800 Leu Leu Ile Val Glu Tyr Ala Lys Tyr Gly Ser Leu
Arg Gly Phe Leu 805 810
815 Arg Glu Ser Arg Lys Val Gly Pro Gly Tyr Leu Gly Ser Gly Gly Ser
820 825 830 Arg Asn Ser
Ser Ser Leu Asp His Pro Asp Glu Arg Ala Leu Thr Met 835
840 845 Gly Asp Leu Ile Ser Phe Ala Trp
Gln Ile Ser Gln Gly Met Gln Tyr 850 855
860 Leu Ala Glu Met Lys Leu Val His Arg Asp Leu Ala Ala
Arg Asn Ile 865 870 875
880 Leu Val Ala Glu Gly Arg Lys Met Lys Ile Ser Asp Phe Gly Leu Ser
885 890 895 Arg Asp Val Tyr
Glu Glu Asp Ser Tyr Val Lys Arg Ser Gln Gly Arg 900
905 910 Ile Pro Val Lys Trp Met Ala Ile Glu
Ser Leu Phe Asp His Ile Tyr 915 920
925 Thr Thr Gln Ser Asp Val Trp Ser Phe Gly Val Leu Leu Trp
Glu Ile 930 935 940
Val Thr Leu Gly Gly Asn Pro Tyr Pro Gly Ile Pro Pro Glu Arg Leu 945
950 955 960 Phe Asn Leu Leu Lys
Thr Gly His Arg Met Glu Arg Pro Asp Asn Cys 965
970 975 Ser Glu Glu Met Tyr Arg Leu Met Leu Gln
Cys Trp Lys Gln Glu Pro 980 985
990 Asp Lys Arg Pro Val Phe Ala Asp Ile Ser Lys Asp Leu Glu
Lys Met 995 1000 1005
Met Val Lys Arg Arg Asp Tyr Leu Asp Leu Ala Ala Ser Thr Pro 1010
1015 1020 Ser Asp Ser Leu Ile
Tyr Asp Asp Gly Leu Ser Glu Glu Glu Thr 1025 1030
1035 Pro Leu Val Asp Cys Asn Asn Ala Pro Leu
Pro Arg Ala Leu Pro 1040 1045 1050
Ser Thr Trp Ile Glu Asn Lys Leu Tyr Gly Met Ser Asp Pro Asn
1055 1060 1065 Trp Pro
Gly Glu Ser Pro Val Pro Leu Thr Arg Ala Asp Gly Thr 1070
1075 1080 Asn Thr Gly Phe Pro Arg Tyr
Pro Asn Asp Ser Val Tyr Ala Asn 1085 1090
1095 Trp Met Leu Ser Pro Ser Ala Ala Lys Leu Met Asp
Thr Phe Asp 1100 1105 1110
Ser 52808DNAHomo sapiensmisc_featureKIF5B-RET (K15;R12 variant 4)
5atggcggacc tggccgagtg caacatcaaa gtgatgtgtc gcttcagacc tctcaacgag
60tctgaagtga accgcggcga caagtacatc gccaagtttc agggagaaga cacggtcgtg
120atcgcgtcca agccttatgc atttgatcgg gtgttccagt caagcacatc tcaagagcaa
180gtgtataatg actgtgcaaa gaagattgtt aaagatgtac ttgaaggata taatggaaca
240atatttgcat atggacaaac atcctctggg aagacacaca caatggaggg taaacttcat
300gatccagaag gcatgggaat tattccaaga atagtgcaag atatttttaa ttatatttac
360tccatggatg aaaatttgga atttcatatt aaggtttcat attttgaaat atatttggat
420aagataaggg acctgttaga tgtttcaaag accaaccttt cagttcatga agacaaaaac
480cgagttccct atgtaaaggg gtgcacagag cgttttgtat gtagtccaga tgaagttatg
540gataccatag atgaaggaaa atccaacaga catgtagcag ttacaaatat gaatgaacat
600agctctagga gtcacagtat atttcttatt aatgtcaaac aagagaacac acaaacggaa
660caaaagctga gtggaaaact ttatctggtt gatttagctg gtagtgaaaa ggttagtaaa
720actggagctg aaggtgctgt gctggatgaa gctaaaaaca tcaacaagtc actttctgct
780cttggaaatg ttatttctgc tttggctgag ggtagtacat atgttccata tcgagatagt
840aaaatgacaa gaatccttca agattcatta ggtggcaact gtagaaccac tattgtaatt
900tgctgctctc catcatcata caatgagtct gaaacaaaat ctacactctt atttggccaa
960agggccaaaa caattaagaa cacagtttgt gtcaatgtgg agttaactgc agaacagtgg
1020aaaaagaagt atgaaaaaga aaaagaaaaa aataagatcc tgcggaacac tattcagtgg
1080cttgaaaatg agctcaacag atggcgtaat ggggagacgg tgcctattga tgaacagttt
1140gacaaagaga aagccaactt ggaagctttc acagtggata aagatattac tcttaccaat
1200gataaaccag caaccgcaat tggagttata ggaaatttta ctgatgctga aagaagaaag
1260tgtgaagaag aaattgctaa attatacaaa cagcttgatg acaaggatga agaaattaac
1320cagcaaagtc aactggtaga gaaactgaag acgcaaatgt tggatcagga ggagcttttg
1380gcatctacca gaagggatca agacaatatg caagctgagc tgaatcgcct tcaagcagaa
1440aatgatgcct ctaaagaaga agtgaaagaa gttttacagg ccctagaaga acttgctgtc
1500aattatgatc agaagtctca ggaagttgaa gacaaaacta aggaatatga attgcttagt
1560gatgaattga atcagaaatc ggcaacttta gcgagtatag atgctgagct tcagaaactt
1620aaggaaatga ccaaccacca gaaaaaacga gcagctgaga tgatggcatc tttactaaaa
1680gaccttgcag aaataggaat tgctgtggga aataatgatg taaaggagga tccaaagtgg
1740gaattccctc ggaagaactt ggttcttgga aaaactctag gagaaggcga atttggaaaa
1800gtggtcaagg caacggcctt ccatctgaaa ggcagagcag ggtacaccac ggtggccgtg
1860aagatgctga aagagaacgc ctccccgagt gagctgcgag acctgctgtc agagttcaac
1920gtcctgaagc aggtcaacca cccacatgtc atcaaattgt atggggcctg cagccaggat
1980ggcccgctcc tcctcatcgt ggagtacgcc aaatacggct ccctgcgggg cttcctccgc
2040gagagccgca aagtggggcc tggctacctg ggcagtggag gcagccgcaa ctccagctcc
2100ctggaccacc cggatgagcg ggccctcacc atgggcgacc tcatctcatt tgcctggcag
2160atctcacagg ggatgcagta tctggccgag atgaagctcg ttcatcggga cttggcagcc
2220agaaacatcc tggtagctga ggggcggaag atgaagattt cggatttcgg cttgtcccga
2280gatgtttatg aagaggattc ctacgtgaag aggagccagg gtcggattcc agttaaatgg
2340atggcaattg aatccctttt tgatcatatc tacaccacgc aaagtgatgt atggtctttt
2400ggtgtcctgc tgtgggagat cgtgacccta gggggaaacc cctatcctgg gattcctcct
2460gagcggctct tcaaccttct gaagaccggc caccggatgg agaggccaga caactgcagc
2520gaggagatgt accgcctgat gctgcaatgc tggaagcagg agccggacaa aaggccggtg
2580tttgcggaca tcagcaaaga cctggagaag atgatggtta agaggagaga ctacttggac
2640cttgcggcgt ccactccatc tgactccctg atttatgacg acggcctctc agaggaggag
2700acaccgctgg tggactgtaa taatgccccc ctccctcgag ccctcccttc cacatggatt
2760gaaaacaaac tctatggtag aatttcccat gcatttacta gattctag
280862997DNAHomo sapiensmisc_featureKIF5B-RET (K16;R12 variant4)
6atggcggacc tggccgagtg caacatcaaa gtgatgtgtc gcttcagacc tctcaacgag
60tctgaagtga accgcggcga caagtacatc gccaagtttc agggagaaga cacggtcgtg
120atcgcgtcca agccttatgc atttgatcgg gtgttccagt caagcacatc tcaagagcaa
180gtgtataatg actgtgcaaa gaagattgtt aaagatgtac ttgaaggata taatggaaca
240atatttgcat atggacaaac atcctctggg aagacacaca caatggaggg taaacttcat
300gatccagaag gcatgggaat tattccaaga atagtgcaag atatttttaa ttatatttac
360tccatggatg aaaatttgga atttcatatt aaggtttcat attttgaaat atatttggat
420aagataaggg acctgttaga tgtttcaaag accaaccttt cagttcatga agacaaaaac
480cgagttccct atgtaaaggg gtgcacagag cgttttgtat gtagtccaga tgaagttatg
540gataccatag atgaaggaaa atccaacaga catgtagcag ttacaaatat gaatgaacat
600agctctagga gtcacagtat atttcttatt aatgtcaaac aagagaacac acaaacggaa
660caaaagctga gtggaaaact ttatctggtt gatttagctg gtagtgaaaa ggttagtaaa
720actggagctg aaggtgctgt gctggatgaa gctaaaaaca tcaacaagtc actttctgct
780cttggaaatg ttatttctgc tttggctgag ggtagtacat atgttccata tcgagatagt
840aaaatgacaa gaatccttca agattcatta ggtggcaact gtagaaccac tattgtaatt
900tgctgctctc catcatcata caatgagtct gaaacaaaat ctacactctt atttggccaa
960agggccaaaa caattaagaa cacagtttgt gtcaatgtgg agttaactgc agaacagtgg
1020aaaaagaagt atgaaaaaga aaaagaaaaa aataagatcc tgcggaacac tattcagtgg
1080cttgaaaatg agctcaacag atggcgtaat ggggagacgg tgcctattga tgaacagttt
1140gacaaagaga aagccaactt ggaagctttc acagtggata aagatattac tcttaccaat
1200gataaaccag caaccgcaat tggagttata ggaaatttta ctgatgctga aagaagaaag
1260tgtgaagaag aaattgctaa attatacaaa cagcttgatg acaaggatga agaaattaac
1320cagcaaagtc aactggtaga gaaactgaag acgcaaatgt tggatcagga ggagcttttg
1380gcatctacca gaagggatca agacaatatg caagctgagc tgaatcgcct tcaagcagaa
1440aatgatgcct ctaaagaaga agtgaaagaa gttttacagg ccctagaaga acttgctgtc
1500aattatgatc agaagtctca ggaagttgaa gacaaaacta aggaatatga attgcttagt
1560gatgaattga atcagaaatc ggcaacttta gcgagtatag atgctgagct tcagaaactt
1620aaggaaatga ccaaccacca gaaaaaacga gcagctgaga tgatggcatc tttactaaaa
1680gaccttgcag aaataggaat tgctgtggga aataatgatg taaagcagcc tgagggaact
1740ggcatgatag atgaagagtt cactgttgca agactctaca ttagcaaaat gaagtcagaa
1800gtaaaaacca tggtgaaacg ttgcaagcag ttagaaagca cacaaactga gagcaacaaa
1860aaaatggaag aaaatgaaaa ggagttagca gcatgtcagc ttcgtatctc tcaagaggat
1920ccaaagtggg aattccctcg gaagaacttg gttcttggaa aaactctagg agaaggcgaa
1980tttggaaaag tggtcaaggc aacggccttc catctgaaag gcagagcagg gtacaccacg
2040gtggccgtga agatgctgaa agagaacgcc tccccgagtg agcttcgaga cctgctgtca
2100gagttcaacg tcctgaagca ggtcaaccac ccacatgtca tcaaattgta tggggcctgc
2160agccaggatg gcccgctcct cctcatcgtg gagtacgcca aatacggctc cctgcggggc
2220ttcctccgcg agagccgcaa agtggggcct ggctacctgg gcagtggagg cagccgcaac
2280tccagctccc tggaccaccc ggatgagcgg gccctcacca tgggcgacct catctcattt
2340gcctggcaga tctcacaggg gatgcagtat ctggccgaga tgaagctcgt tcatcgggac
2400ttggcagcca gaaacatcct ggtagctgag gggcggaaga tgaagatttc ggatttcggc
2460ttgtcccgag atgtttatga agaggattcg tacgtgaaga ggagccaggg tcggattcca
2520gttaaatgga tggcaattga atcccttttt gatcatatct acaccacgca aagtgatgta
2580tggtcttttg gtgtcctgct gtgggagatc gtgaccctag ggggaaaccc ctatcctggg
2640attcctcctg agcggctctt caaccttctg aagaccggcc accggatgga gaggccagac
2700aactgcagcg aggagatgta ccgcctgatg ctgcaatgct ggaagcagga gccggacaaa
2760aggccggtgt ttgcggacat cagcaaagac ctggagaaga tgatggttaa gaggagagac
2820tacttggacc ttgcggcgtc cactccatct gactccctga tttatgacga cggcctctca
2880gaggaggaga caccgctggt ggactgtaat aatgcccccc tccctcgagc cctcccttcc
2940acatggattg aaaacaaact ctatggtaga atttcccatg catttactag attctag
299773522DNAHomo sapiensmisc_featureKIF5B-RET (K22;R12 variant4)
7atggcggacc tggccgagtg caacatcaaa gtgatgtgtc gcttcagacc tctcaacgag
60tctgaagtga accgcggcga caagtacatc gccaagtttc agggagaaga cacggtcgtg
120atcgcgtcca agccttatgc atttgatcgg gtgttccagt caagcacatc tcaagagcaa
180gtgtataatg actgtgcaaa gaagattgtt aaagatgtac ttgaaggata taatggaaca
240atatttgcat atggacaaac atcctctggg aagacacaca caatggaggg taaacttcat
300gatccagaag gcatgggaat tattccaaga atagtgcaag atatttttaa ttatatttac
360tccatggatg aaaatttgga atttcatatt aaggtttcat attttgaaat atatttggat
420aagataaggg acctgttaga tgtttcaaag accaaccttt cagttcatga agacaaaaac
480cgagttccct atgtaaaggg gtgcacagag cgttttgtat gtagtccaga tgaagttatg
540gataccatag atgaaggaaa atccaacaga catgtagcag ttacaaatat gaatgaacat
600agctctagga gtcacagtat atttcttatt aatgtcaaac aagagaacac acaaacggaa
660caaaagctga gtggaaaact ttatctggtt gatttagctg gtagtgaaaa ggttagtaaa
720actggagctg aaggtgctgt gctggatgaa gctaaaaaca tcaacaagtc actttctgct
780cttggaaatg ttatttctgc tttggctgag ggtagtacat atgttccata tcgagatagt
840aaaatgacaa gaatccttca agattcatta ggtggcaact gtagaaccac tattgtaatt
900tgctgctctc catcatcata caatgagtct gaaacaaaat ctacactctt atttggccaa
960agggccaaaa caattaagaa cacagtttgt gtcaatgtgg agttaactgc agaacagtgg
1020aaaaagaagt atgaaaaaga aaaagaaaaa aataagatcc tgcggaacac tattcagtgg
1080cttgaaaatg agctcaacag atggcgtaat ggggagacgg tgcctattga tgaacagttt
1140gacaaagaga aagccaactt ggaagctttc acagtggata aagatattac tcttaccaat
1200gataaaccag caaccgcaat tggagttata ggaaatttta ctgatgctga aagaagaaag
1260tgtgaagaag aaattgctaa attatacaaa cagcttgatg acaaggatga agaaattaac
1320cagcaaagtc aactggtaga gaaactgaag acgcaaatgt tggatcagga ggagcttttg
1380gcatctacca gaagggatca agacaatatg caagctgagc tgaatcgcct tcaagcagaa
1440aatgatgcct ctaaagaaga agtgaaagaa gttttacagg ccctagaaga acttgctgtc
1500aattatgatc agaagtctca ggaagttgaa gacaaaacta aggaatatga attgcttagt
1560gatgaattga atcagaaatc ggcaacttta gcgagtatag atgctgagct tcagaaactt
1620aaggaaatga ccaaccacca gaaaaaacga gcagctgaga tgatggcatc tttactaaaa
1680gaccttgcag aaataggaat tgctgtggga aataatgatg taaagcagcc tgagggaact
1740ggcatgatag atgaagagtt cactgttgca agactctaca ttagcaaaat gaagtcagaa
1800gtaaaaacca tggtgaaacg ttgcaagcag ttagaaagca cacaaactga gagcaacaaa
1860aaaatggaag aaaatgaaaa ggagttagca gcatgtcagc ttcgtatctc tcaacatgaa
1920gccaaaatca agtcattgac tgaatacctt caaaatgtgg aacaaaagaa aagacagttg
1980gaggaatctg tcgatgccct cagtgaagaa ctagtccagc ttcgagcaca agagaaagtc
2040catgaaatgg aaaaggagca cttaaataag gttcagactg caaatgaagt taagcaagct
2100gttgaacagc agatccagag ccatagagaa actcatcaaa aacagatcag tagtttgaga
2160gatgaagtag aagcaaaagc aaaacttatt actgatcttc aagaccaaaa ccagaaaatg
2220atgttagagc aggaacgtct aagagtagaa catgagaagt tgaaagccac agatcaggaa
2280aagagcagaa aactacatga acttacggtt atgcaagata gacgagaaca agcaagacaa
2340gacttgaagg gtttggaaga gacagtggca aaagaacttc agactttaca caacctgcgc
2400aaactctttg ttcaggacct ggctacaaga gttaaaaagg aggatccaaa gtgggaattc
2460cctcggaaga acttggttct tggaaaaact ctaggagaag gcgaatttgg aaaagtggtc
2520aaggcaacgg ccttccatct gaaaggcaga gcagggtaca ccacggtggc cgtgaagatg
2580ctgaaagaga acgcctcccc gagtgagctg cgagacctgc tgtcagagtt caacgtcctg
2640aagcaggtca accacccaca tgtcatcaaa ttgtatgggg cctgcagcca ggatggcccg
2700ctcctcctca tcgtggagta cgccaaatac ggctccctgc ggggcttcct ccgcgagagc
2760cgcaaagtgg ggcctggcta cctgggcagt ggaggcagcc gcaactccag ctccctggac
2820cacccggatg agcgggccct caccatgggc gacctcatct catttgcctg gcagatctca
2880caggggatgc agtatctggc cgagatgaag ctcgttcatc gggacttggc agccagaaac
2940atcctggtag ctgaggggcg gaagatgaag atttcggatt tcggcttgtc ccgagatgtt
3000tatgaagagg attcctacgt gaagaggagc cagggtcgga ttccagttaa atggatggca
3060attgaatccc tttttgatca tatctacacc acgcaaagtg atgtatggtc ttttggtgtc
3120ctgctgtggg agatcgtgac cctaggggga aacccctatc ctgggattcc tcctgagcgg
3180ctcttcaacc ttctgaagac cggccaccgg atggagaggc cagacaactg cagcgaggag
3240atgtaccgcc tgatgctgca atgctggaag caggagccgg acaaaaggcc ggtgtttgcg
3300gacatcagca aagacctgga gaagatgatg gttaagagga gagactactt ggaccttgcg
3360gcgtccactc catctgactc cctgatttat gacgacggcc tctcagagga ggagacaccg
3420ctggtggact gtaataatgc ccccctccct cgagccctcc cttccacatg gattgaaaac
3480aaactctatg gtagaatttc ccatgcattt actagattct ag
352283627DNAHomo sapiensmisc_featureKIF5B-RET (K23;R12 variant4)
8atggcggacc tggccgagtg caacatcaaa gtgatgtgtc gcttcagacc tctcaacgag
60tctgaagtga accgcggcga caagtacatc gccaagtttc agggagaaga cacggtcgtg
120atcgcgtcca agccttatgc atttgatcgg gtgttccagt caagcacatc tcaagagcaa
180gtgtataatg actgtgcaaa gaagattgtt aaagatgtac ttgaaggata taatggaaca
240atatttgcat atggacaaac atcctctggg aagacacaca caatggaggg taaacttcat
300gatccagaag gcatgggaat tattccaaga atagtgcaag atatttttaa ttatatttac
360tccatggatg aaaatttgga atttcatatt aaggtttcat attttgaaat atatttggat
420aagataaggg acctgttaga tgtttcaaag accaaccttt cagttcatga agacaaaaac
480cgagttccct atgtaaaggg gtgcacagag cgttttgtat gtagtccaga tgaagttatg
540gataccatag atgaaggaaa atccaacaga catgtagcag ttacaaatat gaatgaacat
600agctctagga gtcacagtat atttcttatt aatgtcaaac aagagaacac acaaacggaa
660caaaagctga gtggaaaact ttatctggtt gatttagctg gtagtgaaaa ggttagtaaa
720actggagctg aaggtgctgt gctggatgaa gctaaaaaca tcaacaagtc actttctgct
780cttggaaatg ttatttctgc tttggctgag ggtagtacat atgttccata tcgagatagt
840aaaatgacaa gaatccttca agattcatta ggtggcaact gtagaaccac tattgtaatt
900tgctgctctc catcatcata caatgagtct gaaacaaaat ctacactctt atttggccaa
960agggccaaaa caattaagaa cacagtttgt gtcaatgtgg agttaactgc agaacagtgg
1020aaaaagaagt atgaaaaaga aaaagaaaaa aataagatcc tgcggaacac tattcagtgg
1080cttgaaaatg agctcaacag atggcgtaat ggggagacgg tgcctattga tgaacagttt
1140gacaaagaga aagccaactt ggaagctttc acagtggata aagatattac tcttaccaat
1200gataaaccag caaccgcaat tggagttata ggaaatttta ctgatgctga aagaagaaag
1260tgtgaagaag aaattgctaa attatacaaa cagcttgatg acaaggatga agaaattaac
1320cagcaaagtc aactggtaga gaaactgaag acgcaaatgt tggatcagga ggagcttttg
1380gcatctacca gaagggatca agacaatatg caagctgagc tgaatcgcct tcaagcagaa
1440aatgatgcct ctaaagaaga agtgaaagaa gttttacagg ccctagaaga acttgctgtc
1500aattatgatc agaagtctca ggaagttgaa gacaaaacta aggaatatga attgcttagt
1560gatgaattga atcagaaatc ggcaacttta gcgagtatag atgctgagct tcagaaactt
1620aaggaaatga ccaaccacca gaaaaaacga gcagctgaga tgatggcatc tttactaaaa
1680gaccttgcag aaataggaat tgctgtggga aataatgatg taaagcagcc tgagggaact
1740ggcatgatag atgaagagtt cactgttgca agactctaca ttagcaaaat gaagtcagaa
1800gtaaaaacca tggtgaaacg ttgcaagcag ttagaaagca cacaaactga gagcaacaaa
1860aaaatggaag aaaatgaaaa ggagttagca gcatgtcagc ttcgtatctc tcaacatgaa
1920gccaaaatca agtcattgac tgaatacctt caaaatgtgg aacaaaagaa aagacagttg
1980gaggaatctg tcgatgccct cagtgaagaa ctagtccagc ttcgagcaca agagaaagtc
2040catgaaatgg aaaaggagca cttaaataag gttcagactg caaatgaagt taagcaagct
2100gttgaacagc agatccagag ccatagagaa actcatcaaa aacagatcag tagtttgaga
2160gatgaagtag aagcaaaagc aaaacttatt actgatcttc aagaccaaaa ccagaaaatg
2220atgttagagc aggaacgtct aagagtagaa catgagaagt tgaaagccac agatcaggaa
2280aagagcagaa aactacatga acttacggtt atgcaagata gacgagaaca agcaagacaa
2340gacttgaagg gtttggaaga gacagtggca aaagaacttc agactttaca caacctgcgc
2400aaactctttg ttcaggacct ggctacaaga gttaaaaaga gtgctgagat tgattctgat
2460gacaccggag gcagcgctgc tcagaagcaa aaaatctcct ttcttgaaaa taatcttgaa
2520cagctcacta aagtgcacaa acaggaggat ccaaagtggg aattccctcg gaagaacttg
2580gttcttggaa aaactctagg agaaggcgaa tttggaaaag tggtcaaggc aacggccttc
2640catctgaaag gcagagcagg gtacaccacg gtggccgtga agatgctgaa agagaacgcc
2700tccccgagtg agcttcgaga cctgctgtca gagttcaacg tcctgaagca ggtcaaccac
2760ccacatgtca tcaaattgta tggggcctgc agccaggatg gcccgctcct cctcatcgtg
2820gagtacgcca aatacggctc cctgcggggc ttcctccgcg agagccgcaa agtggggcct
2880ggctacctgg gcagtggagg cagccgcaac tccagctccc tggaccaccc ggatgagcgg
2940gccctcacca tgggcgacct catctcattt gcctggcaga tctcacaggg gatgcagtat
3000ctggccgaga tgaagctcgt tcatcgggac ttggcagcca gaaacatcct ggtagctgag
3060gggcggaaga tgaagatttc ggatttcggc ttgtcccgag atgtttatga agaggattcc
3120tacgtgaaga ggagccaggg tcggattcca gttaaatgga tggcaattga atcccttttt
3180gatcatatct acaccacgca aagtgatgta tggtcttttg gtgtcctgct gtgggagatc
3240gtgaccctag ggggaaaccc ctatcctggg attcctcctg agcggctctt caaccttctg
3300aagaccggcc accggatgga gaggccagac aactgcagcg aggagatgta ccgcctgatg
3360ctgcaatgct ggaagcagga gccggacaaa aggccggtgt ttgcggacat cagcaaagac
3420ctggagaaga tgatggttaa gaggagagac tacttggacc ttgcggcgtc cactccatct
3480gactccctga tttatgacga cggcctctca gaggaggaga caccgctggt ggactgtaat
3540aatgcccccc tccctcgagc cctcccttcc acatggattg aaaacaaact ctatggtaga
3600atttcccatg catttactag attctag
362794101DNAHomo sapiensmisc_featureKIF5B-RET (K24;R11 variant4)
9atggcggacc tggccgagtg caacatcaaa gtgatgtgtc gcttcagacc tctcaacgag
60tctgaagtga accgcggcga caagtacatc gccaagtttc agggagaaga cacggtcgtg
120atcgcgtcca agccttatgc atttgatcgg gtgttccagt caagcacatc tcaagagcaa
180gtgtataatg actgtgcaaa gaagattgtt aaagatgtac ttgaaggata taatggaaca
240atatttgcat atggacaaac atcctctggg aagacacaca caatggaggg taaacttcat
300gatccagaag gcatgggaat tattccaaga atagtgcaag atatttttaa ttatatttac
360tccatggatg aaaatttgga atttcatatt aaggtttcat attttgaaat atatttggat
420aagataaggg acctgttaga tgtttcaaag accaaccttt cagttcatga agacaaaaac
480cgagttccct atgtaaaggg gtgcacagag cgttttgtat gtagtccaga tgaagttatg
540gataccatag atgaaggaaa atccaacaga catgtagcag ttacaaatat gaatgaacat
600agctctagga gtcacagtat atttcttatt aatgtcaaac aagagaacac acaaacggaa
660caaaagctga gtggaaaact ttatctggtt gatttagctg gtagtgaaaa ggttagtaaa
720actggagctg aaggtgctgt gctggatgaa gctaaaaaca tcaacaagtc actttctgct
780cttggaaatg ttatttctgc tttggctgag ggtagtacat atgttccata tcgagatagt
840aaaatgacaa gaatccttca agattcatta ggtggcaact gtagaaccac tattgtaatt
900tgctgctctc catcatcata caatgagtct gaaacaaaat ctacactctt atttggccaa
960agggccaaaa caattaagaa cacagtttgt gtcaatgtgg agttaactgc agaacagtgg
1020aaaaagaagt atgaaaaaga aaaagaaaaa aataagatcc tgcggaacac tattcagtgg
1080cttgaaaatg agctcaacag atggcgtaat ggggagacgg tgcctattga tgaacagttt
1140gacaaagaga aagccaactt ggaagctttc acagtggata aagatattac tcttaccaat
1200gataaaccag caaccgcaat tggagttata ggaaatttta ctgatgctga aagaagaaag
1260tgtgaagaag aaattgctaa attatacaaa cagcttgatg acaaggatga agaaattaac
1320cagcaaagtc aactggtaga gaaactgaag acgcaaatgt tggatcagga ggagcttttg
1380gcatctacca gaagggatca agacaatatg caagctgagc tgaatcgcct tcaagcagaa
1440aatgatgcct ctaaagaaga agtgaaagaa gttttacagg ccctagaaga acttgctgtc
1500aattatgatc agaagtctca ggaagttgaa gacaaaacta aggaatatga attgcttagt
1560gatgaattga atcagaaatc ggcaacttta gcgagtatag atgctgagct tcagaaactt
1620aaggaaatga ccaaccacca gaaaaaacga gcagctgaga tgatggcatc tttactaaaa
1680gaccttgcag aaataggaat tgctgtggga aataatgatg taaagcagcc tgagggaact
1740ggcatgatag atgaagagtt cactgttgca agactctaca ttagcaaaat gaagtcagaa
1800gtaaaaacca tggtgaaacg ttgcaagcag ttagaaagca cacaaactga gagcaacaaa
1860aaaatggaag aaaatgaaaa ggagttagca gcatgtcagc ttcgtatctc tcaacatgaa
1920gccaaaatca agtcattgac tgaatacctt caaaatgtgg aacaaaagaa aagacagttg
1980gaggaatctg tcgatgccct cagtgaagaa ctagtccagc ttcgagcaca agagaaagtc
2040catgaaatgg aaaaggagca cttaaataag gttcagactg caaatgaagt taagcaagct
2100gttgaacagc agatccagag ccatagagaa actcatcaaa aacagatcag tagtttgaga
2160gatgaagtag aagcaaaagc aaaacttatt actgatcttc aagaccaaaa ccagaaaatg
2220atgttagagc aggaacgtct aagagtagaa catgagaagt tgaaagccac agatcaggaa
2280aagagcagaa aactacatga acttacggtt atgcaagata gacgagaaca agcaagacaa
2340gacttgaagg gtttggaaga gacagtggca aaagaacttc agactttaca caacctgcgc
2400aaactctttg ttcaggacct ggctacaaga gttaaaaaga gtgctgagat tgattctgat
2460gacaccggag gcagcgctgc tcagaagcaa aaaatctcct ttcttgaaaa taatcttgaa
2520cagctcacta aagtgcacaa acagttggta cgtgataatg cagatctccg ctgtgaactt
2580cctaagttgg aaaagcgact tcgagctaca gctgagagag tgaaagcttt ggaatcagca
2640ctgaaagaag ctaaagaaaa tgcatctcgt gatcgcaaac gctatcagca agaagtagat
2700cgcataaagg aagcagtcag gtcaaagaat atggccagaa gagggcattc tgcacagatt
2760gatccactgt gcgacgagct gtgccgcacg gtgatcgcag ccgctgtcct cttctccttc
2820atcgtctcgg tgctgctgtc tgccttctgc atccactgct accacaagtt tgcccacaag
2880ccacccatct cctcagctga gatgaccttc cggaggcccg cccaggcctt cccggtcagc
2940tactcctctt ccggtgcccg ccggccctcg ctggactcca tggagaacca ggtctccgtg
3000gatgccttca agatcctgga ggatccaaag tgggaattcc ctcggaagaa cttggttctt
3060ggaaaaactc taggagaagg cgaatttgga aaagtggtca aggcaacggc cttccatctg
3120aaaggcagag cagggtacac cacggtggcc gtgaagatgc tgaaagagaa cgcctccccg
3180agtgagcttc gagacctgct gtcagagttc aacgtcctga agcaggtcaa ccacccacat
3240gtcatcaaat tgtatggggc ctgcagccag gatggcccgc tcctcctcat cgtggagtac
3300gccaaatacg gctccctgcg gggcttcctc cgcgagagcc gcaaagtggg gcctggctac
3360ctgggcagtg gaggcagccg caactccagc tccctggacc acccggatga gcgggccctc
3420accatgggcg acctcatctc atttgcctgg cagatctcac aggggatgca gtatctggcc
3480gagatgaagc tcgttcatcg ggacttggca gccagaaaca tcctggtagc tgaggggcgg
3540aagatgaaga tttcggattt cggcttgtcc cgagatgttt atgaagagga ttcctacgtg
3600aagaggagcc agggtcggat tccagttaaa tggatggcaa ttgaatccct ttttgatcat
3660atctacacca cgcaaagtga tgtatggtct tttggtgtcc tgctgtggga gatcgtgacc
3720ctagggggaa acccctatcc tgggattcct cctgagcggc tcttcaacct tctgaagacc
3780ggccaccgga tggagaggcc agacaactgc agcgaggaga tgtaccgcct gatgctgcaa
3840tgctggaagc aggagccgga caaaaggccg gtgtttgcgg acatcagcaa agacctggag
3900aagatgatgg ttaagaggag agactacttg gaccttgcgg cgtccactcc atctgactcc
3960ctgatttatg acgacggcct ctcagaggag gagacaccgc tggtggactg taataatgcc
4020cccctccctc gagccctccc ttccacatgg attgaaaaca aactctatgg tagaatttcc
4080catgcattta ctagattcta g
4101102934DNAHomo sapiensmisc_featureKIF5B-RET (K15;R12 variant2)
10atggcggacc tggccgagtg caacatcaaa gtgatgtgtc gcttcagacc tctcaacgag
60tctgaagtga accgcggcga caagtacatc gccaagtttc agggagaaga cacggtcgtg
120atcgcgtcca agccttatgc atttgatcgg gtgttccagt caagcacatc tcaagagcaa
180gtgtataatg actgtgcaaa gaagattgtt aaagatgtac ttgaaggata taatggaaca
240atatttgcat atggacaaac atcctctggg aagacacaca caatggaggg taaacttcat
300gatccagaag gcatgggaat tattccaaga atagtgcaag atatttttaa ttatatttac
360tccatggatg aaaatttgga atttcatatt aaggtttcat attttgaaat atatttggat
420aagataaggg acctgttaga tgtttcaaag accaaccttt cagttcatga agacaaaaac
480cgagttccct atgtaaaggg gtgcacagag cgttttgtat gtagtccaga tgaagttatg
540gataccatag atgaaggaaa atccaacaga catgtagcag ttacaaatat gaatgaacat
600agctctagga gtcacagtat atttcttatt aatgtcaaac aagagaacac acaaacggaa
660caaaagctga gtggaaaact ttatctggtt gatttagctg gtagtgaaaa ggttagtaaa
720actggagctg aaggtgctgt gctggatgaa gctaaaaaca tcaacaagtc actttctgct
780cttggaaatg ttatttctgc tttggctgag ggtagtacat atgttccata tcgagatagt
840aaaatgacaa gaatccttca agattcatta ggtggcaact gtagaaccac tattgtaatt
900tgctgctctc catcatcata caatgagtct gaaacaaaat ctacactctt atttggccaa
960agggccaaaa caattaagaa cacagtttgt gtcaatgtgg agttaactgc agaacagtgg
1020aaaaagaagt atgaaaaaga aaaagaaaaa aataagatcc tgcggaacac tattcagtgg
1080cttgaaaatg agctcaacag atggcgtaat ggggagacgg tgcctattga tgaacagttt
1140gacaaagaga aagccaactt ggaagctttc acagtggata aagatattac tcttaccaat
1200gataaaccag caaccgcaat tggagttata ggaaatttta ctgatgctga aagaagaaag
1260tgtgaagaag aaattgctaa attatacaaa cagcttgatg acaaggatga agaaattaac
1320cagcaaagtc aactggtaga gaaactgaag acgcaaatgt tggatcagga ggagcttttg
1380gcatctacca gaagggatca agacaatatg caagctgagc tgaatcgcct tcaagcagaa
1440aatgatgcct ctaaagaaga agtgaaagaa gttttacagg ccctagaaga acttgctgtc
1500aattatgatc agaagtctca ggaagttgaa gacaaaacta aggaatatga attgcttagt
1560gatgaattga atcagaaatc ggcaacttta gcgagtatag atgctgagct tcagaaactt
1620aaggaaatga ccaaccacca gaaaaaacga gcagctgaga tgatggcatc tttactaaaa
1680gaccttgcag aaataggaat tgctgtggga aataatgatg taaaggagga tccaaagtgg
1740gaattccctc ggaagaactt ggttcttgga aaaactctag gagaaggcga atttggaaaa
1800gtggtcaagg caacggcctt ccatctgaaa ggcagagcag ggtacaccac ggtggccgtg
1860aagatgctga aagagaacgc ctccccgagt gagctgcgag acctgctgtc agagttcaac
1920gtcctgaagc aggtcaacca cccacatgtc atcaaattgt atggggcctg cagccaggat
1980ggcccgctcc tcctcatcgt ggagtacgcc aaatacggct ccctgcgggg cttcctccgc
2040gagagccgca aagtggggcc tggctacctg ggcagtggag gcagccgcaa ctccagctcc
2100ctggaccacc cggatgagcg ggccctcacc atgggcgacc tcatctcatt tgcctggcag
2160atctcacagg ggatgcagta tctggccgag atgaagctcg ttcatcggga cttggcagcc
2220agaaacatcc tggtagctga ggggcggaag atgaagattt cggatttcgg cttgtcccga
2280gatgtttatg aagaggattc ctacgtgaag aggagccagg gtcggattcc agttaaatgg
2340atggcaattg aatccctttt tgatcatatc tacaccacgc aaagtgatgt atggtctttt
2400ggtgtcctgc tgtgggagat cgtgacccta gggggaaacc cctatcctgg gattcctcct
2460gagcggctct tcaaccttct gaagaccggc caccggatgg agaggccaga caactgcagc
2520gaggagatgt accgcctgat gctgcaatgc tggaagcagg agccggacaa aaggccggtg
2580tttgcggaca tcagcaaaga cctggagaag atgatggtta agaggagaga ctacttggac
2640cttgcggcgt ccactccatc tgactccctg atttatgacg acggcctctc agaggaggag
2700acaccgctgg tggactgtaa taatgccccc ctccctcgag ccctcccttc cacatggatt
2760gaaaacaaac tctatggcat gtcagacccg aactggcctg gagagagtcc tgtaccactc
2820acgagagctg atggcactaa cactgggttt ccaagatatc caaatgatag tgtatatgct
2880aactggatgc tttcaccctc agcggcaaaa ttaatggaca cgtttgatag ttaa
2934113123DNAHomo sapiensmisc_featureKIF5B-RET (K16;R12 variant2)
11atggcggacc tggccgagtg caacatcaaa gtgatgtgtc gcttcagacc tctcaacgag
60tctgaagtga accgcggcga caagtacatc gccaagtttc agggagaaga cacggtcgtg
120atcgcgtcca agccttatgc atttgatcgg gtgttccagt caagcacatc tcaagagcaa
180gtgtataatg actgtgcaaa gaagattgtt aaagatgtac ttgaaggata taatggaaca
240atatttgcat atggacaaac atcctctggg aagacacaca caatggaggg taaacttcat
300gatccagaag gcatgggaat tattccaaga atagtgcaag atatttttaa ttatatttac
360tccatggatg aaaatttgga atttcatatt aaggtttcat attttgaaat atatttggat
420aagataaggg acctgttaga tgtttcaaag accaaccttt cagttcatga agacaaaaac
480cgagttccct atgtaaaggg gtgcacagag cgttttgtat gtagtccaga tgaagttatg
540gataccatag atgaaggaaa atccaacaga catgtagcag ttacaaatat gaatgaacat
600agctctagga gtcacagtat atttcttatt aatgtcaaac aagagaacac acaaacggaa
660caaaagctga gtggaaaact ttatctggtt gatttagctg gtagtgaaaa ggttagtaaa
720actggagctg aaggtgctgt gctggatgaa gctaaaaaca tcaacaagtc actttctgct
780cttggaaatg ttatttctgc tttggctgag ggtagtacat atgttccata tcgagatagt
840aaaatgacaa gaatccttca agattcatta ggtggcaact gtagaaccac tattgtaatt
900tgctgctctc catcatcata caatgagtct gaaacaaaat ctacactctt atttggccaa
960agggccaaaa caattaagaa cacagtttgt gtcaatgtgg agttaactgc agaacagtgg
1020aaaaagaagt atgaaaaaga aaaagaaaaa aataagatcc tgcggaacac tattcagtgg
1080cttgaaaatg agctcaacag atggcgtaat ggggagacgg tgcctattga tgaacagttt
1140gacaaagaga aagccaactt ggaagctttc acagtggata aagatattac tcttaccaat
1200gataaaccag caaccgcaat tggagttata ggaaatttta ctgatgctga aagaagaaag
1260tgtgaagaag aaattgctaa attatacaaa cagcttgatg acaaggatga agaaattaac
1320cagcaaagtc aactggtaga gaaactgaag acgcaaatgt tggatcagga ggagcttttg
1380gcatctacca gaagggatca agacaatatg caagctgagc tgaatcgcct tcaagcagaa
1440aatgatgcct ctaaagaaga agtgaaagaa gttttacagg ccctagaaga acttgctgtc
1500aattatgatc agaagtctca ggaagttgaa gacaaaacta aggaatatga attgcttagt
1560gatgaattga atcagaaatc ggcaacttta gcgagtatag atgctgagct tcagaaactt
1620aaggaaatga ccaaccacca gaaaaaacga gcagctgaga tgatggcatc tttactaaaa
1680gaccttgcag aaataggaat tgctgtggga aataatgatg taaagcagcc tgagggaact
1740ggcatgatag atgaagagtt cactgttgca agactctaca ttagcaaaat gaagtcagaa
1800gtaaaaacca tggtgaaacg ttgcaagcag ttagaaagca cacaaactga gagcaacaaa
1860aaaatggaag aaaatgaaaa ggagttagca gcatgtcagc ttcgtatctc tcaagaggat
1920ccaaagtggg aattccctcg gaagaacttg gttcttggaa aaactctagg agaaggcgaa
1980tttggaaaag tggtcaaggc aacggccttc catctgaaag gcagagcagg gtacaccacg
2040gtggccgtga agatgctgaa agagaacgcc tccccgagtg agcttcgaga cctgctgtca
2100gagttcaacg tcctgaagca ggtcaaccac ccacatgtca tcaaattgta tggggcctgc
2160agccaggatg gcccgctcct cctcatcgtg gagtacgcca aatacggctc cctgcggggc
2220ttcctccgcg agagccgcaa agtggggcct ggctacctgg gcagtggagg cagccgcaac
2280tccagctccc tggaccaccc ggatgagcgg gccctcacca tgggcgacct catctcattt
2340gcctggcaga tctcacaggg gatgcagtat ctggccgaga tgaagctcgt tcatcgggac
2400ttggcagcca gaaacatcct ggtagctgag gggcggaaga tgaagatttc ggatttcggc
2460ttgtcccgag atgtttatga agaggattcg tacgtgaaga ggagccaggg tcggattcca
2520gttaaatgga tggcaattga atcccttttt gatcatatct acaccacgca aagtgatgta
2580tggtcttttg gtgtcctgct gtgggagatc gtgaccctag ggggaaaccc ctatcctggg
2640attcctcctg agcggctctt caaccttctg aagaccggcc accggatgga gaggccagac
2700aactgcagcg aggagatgta ccgcctgatg ctgcaatgct ggaagcagga gccggacaaa
2760aggccggtgt ttgcggacat cagcaaagac ctggagaaga tgatggttaa gaggagagac
2820tacttggacc ttgcggcgtc cactccatct gactccctga tttatgacga cggcctctca
2880gaggaggaga caccgctggt ggactgtaat aatgcccccc tccctcgagc cctcccttcc
2940acatggattg aaaacaaact ctatggcatg tcagacccga actggcctgg agagagtcct
3000gtaccactca cgagagctga tggcactaac actgggtttc caagatatcc aaatgatagt
3060gtatatgcta actggatgct ttcaccctca gcggcaaaat taatggacac gtttgatagt
3120taa
3123123648DNAHomo sapiensmisc_featureKIF5B-RET (K22;R12 variant2)
12atggcggacc tggccgagtg caacatcaaa gtgatgtgtc gcttcagacc tctcaacgag
60tctgaagtga accgcggcga caagtacatc gccaagtttc agggagaaga cacggtcgtg
120atcgcgtcca agccttatgc atttgatcgg gtgttccagt caagcacatc tcaagagcaa
180gtgtataatg actgtgcaaa gaagattgtt aaagatgtac ttgaaggata taatggaaca
240atatttgcat atggacaaac atcctctggg aagacacaca caatggaggg taaacttcat
300gatccagaag gcatgggaat tattccaaga atagtgcaag atatttttaa ttatatttac
360tccatggatg aaaatttgga atttcatatt aaggtttcat attttgaaat atatttggat
420aagataaggg acctgttaga tgtttcaaag accaaccttt cagttcatga agacaaaaac
480cgagttccct atgtaaaggg gtgcacagag cgttttgtat gtagtccaga tgaagttatg
540gataccatag atgaaggaaa atccaacaga catgtagcag ttacaaatat gaatgaacat
600agctctagga gtcacagtat atttcttatt aatgtcaaac aagagaacac acaaacggaa
660caaaagctga gtggaaaact ttatctggtt gatttagctg gtagtgaaaa ggttagtaaa
720actggagctg aaggtgctgt gctggatgaa gctaaaaaca tcaacaagtc actttctgct
780cttggaaatg ttatttctgc tttggctgag ggtagtacat atgttccata tcgagatagt
840aaaatgacaa gaatccttca agattcatta ggtggcaact gtagaaccac tattgtaatt
900tgctgctctc catcatcata caatgagtct gaaacaaaat ctacactctt atttggccaa
960agggccaaaa caattaagaa cacagtttgt gtcaatgtgg agttaactgc agaacagtgg
1020aaaaagaagt atgaaaaaga aaaagaaaaa aataagatcc tgcggaacac tattcagtgg
1080cttgaaaatg agctcaacag atggcgtaat ggggagacgg tgcctattga tgaacagttt
1140gacaaagaga aagccaactt ggaagctttc acagtggata aagatattac tcttaccaat
1200gataaaccag caaccgcaat tggagttata ggaaatttta ctgatgctga aagaagaaag
1260tgtgaagaag aaattgctaa attatacaaa cagcttgatg acaaggatga agaaattaac
1320cagcaaagtc aactggtaga gaaactgaag acgcaaatgt tggatcagga ggagcttttg
1380gcatctacca gaagggatca agacaatatg caagctgagc tgaatcgcct tcaagcagaa
1440aatgatgcct ctaaagaaga agtgaaagaa gttttacagg ccctagaaga acttgctgtc
1500aattatgatc agaagtctca ggaagttgaa gacaaaacta aggaatatga attgcttagt
1560gatgaattga atcagaaatc ggcaacttta gcgagtatag atgctgagct tcagaaactt
1620aaggaaatga ccaaccacca gaaaaaacga gcagctgaga tgatggcatc tttactaaaa
1680gaccttgcag aaataggaat tgctgtggga aataatgatg taaagcagcc tgagggaact
1740ggcatgatag atgaagagtt cactgttgca agactctaca ttagcaaaat gaagtcagaa
1800gtaaaaacca tggtgaaacg ttgcaagcag ttagaaagca cacaaactga gagcaacaaa
1860aaaatggaag aaaatgaaaa ggagttagca gcatgtcagc ttcgtatctc tcaacatgaa
1920gccaaaatca agtcattgac tgaatacctt caaaatgtgg aacaaaagaa aagacagttg
1980gaggaatctg tcgatgccct cagtgaagaa ctagtccagc ttcgagcaca agagaaagtc
2040catgaaatgg aaaaggagca cttaaataag gttcagactg caaatgaagt taagcaagct
2100gttgaacagc agatccagag ccatagagaa actcatcaaa aacagatcag tagtttgaga
2160gatgaagtag aagcaaaagc aaaacttatt actgatcttc aagaccaaaa ccagaaaatg
2220atgttagagc aggaacgtct aagagtagaa catgagaagt tgaaagccac agatcaggaa
2280aagagcagaa aactacatga acttacggtt atgcaagata gacgagaaca agcaagacaa
2340gacttgaagg gtttggaaga gacagtggca aaagaacttc agactttaca caacctgcgc
2400aaactctttg ttcaggacct ggctacaaga gttaaaaagg aggatccaaa gtgggaattc
2460cctcggaaga acttggttct tggaaaaact ctaggagaag gcgaatttgg aaaagtggtc
2520aaggcaacgg ccttccatct gaaaggcaga gcagggtaca ccacggtggc cgtgaagatg
2580ctgaaagaga acgcctcccc gagtgagctg cgagacctgc tgtcagagtt caacgtcctg
2640aagcaggtca accacccaca tgtcatcaaa ttgtatgggg cctgcagcca ggatggcccg
2700ctcctcctca tcgtggagta cgccaaatac ggctccctgc ggggcttcct ccgcgagagc
2760cgcaaagtgg ggcctggcta cctgggcagt ggaggcagcc gcaactccag ctccctggac
2820cacccggatg agcgggccct caccatgggc gacctcatct catttgcctg gcagatctca
2880caggggatgc agtatctggc cgagatgaag ctcgttcatc gggacttggc agccagaaac
2940atcctggtag ctgaggggcg gaagatgaag atttcggatt tcggcttgtc ccgagatgtt
3000tatgaagagg attcctacgt gaagaggagc cagggtcgga ttccagttaa atggatggca
3060attgaatccc tttttgatca tatctacacc acgcaaagtg atgtatggtc ttttggtgtc
3120ctgctgtggg agatcgtgac cctaggggga aacccctatc ctgggattcc tcctgagcgg
3180ctcttcaacc ttctgaagac cggccaccgg atggagaggc cagacaactg cagcgaggag
3240atgtaccgcc tgatgctgca atgctggaag caggagccgg acaaaaggcc ggtgtttgcg
3300gacatcagca aagacctgga gaagatgatg gttaagagga gagactactt ggaccttgcg
3360gcgtccactc catctgactc cctgatttat gacgacggcc tctcagagga ggagacaccg
3420ctggtggact gtaataatgc ccccctccct cgagccctcc cttccacatg gattgaaaac
3480aaactctatg gcatgtcaga cccgaactgg cctggagaga gtcctgtacc actcacgaga
3540gctgatggca ctaacactgg gtttccaaga tatccaaatg atagtgtata tgctaactgg
3600atgctttcac cctcagcggc aaaattaatg gacacgtttg atagttaa
3648133753DNAHomo sapiensmisc_featureKIF5B-RET (K23;R12 variant2)
13atggcggacc tggccgagtg caacatcaaa gtgatgtgtc gcttcagacc tctcaacgag
60tctgaagtga accgcggcga caagtacatc gccaagtttc agggagaaga cacggtcgtg
120atcgcgtcca agccttatgc atttgatcgg gtgttccagt caagcacatc tcaagagcaa
180gtgtataatg actgtgcaaa gaagattgtt aaagatgtac ttgaaggata taatggaaca
240atatttgcat atggacaaac atcctctggg aagacacaca caatggaggg taaacttcat
300gatccagaag gcatgggaat tattccaaga atagtgcaag atatttttaa ttatatttac
360tccatggatg aaaatttgga atttcatatt aaggtttcat attttgaaat atatttggat
420aagataaggg acctgttaga tgtttcaaag accaaccttt cagttcatga agacaaaaac
480cgagttccct atgtaaaggg gtgcacagag cgttttgtat gtagtccaga tgaagttatg
540gataccatag atgaaggaaa atccaacaga catgtagcag ttacaaatat gaatgaacat
600agctctagga gtcacagtat atttcttatt aatgtcaaac aagagaacac acaaacggaa
660caaaagctga gtggaaaact ttatctggtt gatttagctg gtagtgaaaa ggttagtaaa
720actggagctg aaggtgctgt gctggatgaa gctaaaaaca tcaacaagtc actttctgct
780cttggaaatg ttatttctgc tttggctgag ggtagtacat atgttccata tcgagatagt
840aaaatgacaa gaatccttca agattcatta ggtggcaact gtagaaccac tattgtaatt
900tgctgctctc catcatcata caatgagtct gaaacaaaat ctacactctt atttggccaa
960agggccaaaa caattaagaa cacagtttgt gtcaatgtgg agttaactgc agaacagtgg
1020aaaaagaagt atgaaaaaga aaaagaaaaa aataagatcc tgcggaacac tattcagtgg
1080cttgaaaatg agctcaacag atggcgtaat ggggagacgg tgcctattga tgaacagttt
1140gacaaagaga aagccaactt ggaagctttc acagtggata aagatattac tcttaccaat
1200gataaaccag caaccgcaat tggagttata ggaaatttta ctgatgctga aagaagaaag
1260tgtgaagaag aaattgctaa attatacaaa cagcttgatg acaaggatga agaaattaac
1320cagcaaagtc aactggtaga gaaactgaag acgcaaatgt tggatcagga ggagcttttg
1380gcatctacca gaagggatca agacaatatg caagctgagc tgaatcgcct tcaagcagaa
1440aatgatgcct ctaaagaaga agtgaaagaa gttttacagg ccctagaaga acttgctgtc
1500aattatgatc agaagtctca ggaagttgaa gacaaaacta aggaatatga attgcttagt
1560gatgaattga atcagaaatc ggcaacttta gcgagtatag atgctgagct tcagaaactt
1620aaggaaatga ccaaccacca gaaaaaacga gcagctgaga tgatggcatc tttactaaaa
1680gaccttgcag aaataggaat tgctgtggga aataatgatg taaagcagcc tgagggaact
1740ggcatgatag atgaagagtt cactgttgca agactctaca ttagcaaaat gaagtcagaa
1800gtaaaaacca tggtgaaacg ttgcaagcag ttagaaagca cacaaactga gagcaacaaa
1860aaaatggaag aaaatgaaaa ggagttagca gcatgtcagc ttcgtatctc tcaacatgaa
1920gccaaaatca agtcattgac tgaatacctt caaaatgtgg aacaaaagaa aagacagttg
1980gaggaatctg tcgatgccct cagtgaagaa ctagtccagc ttcgagcaca agagaaagtc
2040catgaaatgg aaaaggagca cttaaataag gttcagactg caaatgaagt taagcaagct
2100gttgaacagc agatccagag ccatagagaa actcatcaaa aacagatcag tagtttgaga
2160gatgaagtag aagcaaaagc aaaacttatt actgatcttc aagaccaaaa ccagaaaatg
2220atgttagagc aggaacgtct aagagtagaa catgagaagt tgaaagccac agatcaggaa
2280aagagcagaa aactacatga acttacggtt atgcaagata gacgagaaca agcaagacaa
2340gacttgaagg gtttggaaga gacagtggca aaagaacttc agactttaca caacctgcgc
2400aaactctttg ttcaggacct ggctacaaga gttaaaaaga gtgctgagat tgattctgat
2460gacaccggag gcagcgctgc tcagaagcaa aaaatctcct ttcttgaaaa taatcttgaa
2520cagctcacta aagtgcacaa acaggaggat ccaaagtggg aattccctcg gaagaacttg
2580gttcttggaa aaactctagg agaaggcgaa tttggaaaag tggtcaaggc aacggccttc
2640catctgaaag gcagagcagg gtacaccacg gtggccgtga agatgctgaa agagaacgcc
2700tccccgagtg agcttcgaga cctgctgtca gagttcaacg tcctgaagca ggtcaaccac
2760ccacatgtca tcaaattgta tggggcctgc agccaggatg gcccgctcct cctcatcgtg
2820gagtacgcca aatacggctc cctgcggggc ttcctccgcg agagccgcaa agtggggcct
2880ggctacctgg gcagtggagg cagccgcaac tccagctccc tggaccaccc ggatgagcgg
2940gccctcacca tgggcgacct catctcattt gcctggcaga tctcacaggg gatgcagtat
3000ctggccgaga tgaagctcgt tcatcgggac ttggcagcca gaaacatcct ggtagctgag
3060gggcggaaga tgaagatttc ggatttcggc ttgtcccgag atgtttatga agaggattcc
3120tacgtgaaga ggagccaggg tcggattcca gttaaatgga tggcaattga atcccttttt
3180gatcatatct acaccacgca aagtgatgta tggtcttttg gtgtcctgct gtgggagatc
3240gtgaccctag ggggaaaccc ctatcctggg attcctcctg agcggctctt caaccttctg
3300aagaccggcc accggatgga gaggccagac aactgcagcg aggagatgta ccgcctgatg
3360ctgcaatgct ggaagcagga gccggacaaa aggccggtgt ttgcggacat cagcaaagac
3420ctggagaaga tgatggttaa gaggagagac tacttggacc ttgcggcgtc cactccatct
3480gactccctga tttatgacga cggcctctca gaggaggaga caccgctggt ggactgtaat
3540aatgcccccc tccctcgagc cctcccttcc acatggattg aaaacaaact ctatggcatg
3600tcagacccga actggcctgg agagagtcct gtaccactca cgagagctga tggcactaac
3660actgggtttc caagatatcc aaatgatagt gtatatgcta actggatgct ttcaccctca
3720gcggcaaaat taatggacac gtttgatagt taa
3753142958DNAHomo sapiensmisc_featureKIF5B-RET (K15;R11 variant4)
14atggcggacc tggccgagtg caacatcaaa gtgatgtgtc gcttcagacc tctcaacgag
60tctgaagtga accgcggcga caagtacatc gccaagtttc agggagaaga cacggtcgtg
120atcgcgtcca agccttatgc atttgatcgg gtgttccagt caagcacatc tcaagagcaa
180gtgtataatg actgtgcaaa gaagattgtt aaagatgtac ttgaaggata taatggaaca
240atatttgcat atggacaaac atcctctggg aagacacaca caatggaggg taaacttcat
300gatccagaag gcatgggaat tattccaaga atagtgcaag atatttttaa ttatatttac
360tccatggatg aaaatttgga atttcatatt aaggtttcat attttgaaat atatttggat
420aagataaggg acctgttaga tgtttcaaag accaaccttt cagttcatga agacaaaaac
480cgagttccct atgtaaaggg gtgcacagag cgttttgtat gtagtccaga tgaagttatg
540gataccatag atgaaggaaa atccaacaga catgtagcag ttacaaatat gaatgaacat
600agctctagga gtcacagtat atttcttatt aatgtcaaac aagagaacac acaaacggaa
660caaaagctga gtggaaaact ttatctggtt gatttagctg gtagtgaaaa ggttagtaaa
720actggagctg aaggtgctgt gctggatgaa gctaaaaaca tcaacaagtc actttctgct
780cttggaaatg ttatttctgc tttggctgag ggtagtacat atgttccata tcgagatagt
840aaaatgacaa gaatccttca agattcatta ggtggcaact gtagaaccac tattgtaatt
900tgctgctctc catcatcata caatgagtct gaaacaaaat ctacactctt atttggccaa
960agggccaaaa caattaagaa cacagtttgt gtcaatgtgg agttaactgc agaacagtgg
1020aaaaagaagt atgaaaaaga aaaagaaaaa aataagatcc tgcggaacac tattcagtgg
1080cttgaaaatg agctcaacag atggcgtaat ggggagacgg tgcctattga tgaacagttt
1140gacaaagaga aagccaactt ggaagctttc acagtggata aagatattac tcttaccaat
1200gataaaccag caaccgcaat tggagttata ggaaatttta ctgatgctga aagaagaaag
1260tgtgaagaag aaattgctaa attatacaaa cagcttgatg acaaggatga agaaattaac
1320cagcaaagtc aactggtaga gaaactgaag acgcaaatgt tggatcagga ggagcttttg
1380gcatctacca gaagggatca agacaatatg caagctgagc tgaatcgcct tcaagcagaa
1440aatgatgcct ctaaagaaga agtgaaagaa gttttacagg ccctagaaga acttgctgtc
1500aattatgatc agaagtctca ggaagttgaa gacaaaacta aggaatatga attgcttagt
1560gatgaattga atcagaaatc ggcaacttta gcgagtatag atgctgagct tcagaaactt
1620aaggaaatga ccaaccacca gaaaaaacga gcagctgaga tgatggcatc tttactaaaa
1680gaccttgcag aaataggaat tgctgtggga aataatgatg taaagtttgc ccacaagcca
1740cccatctcct cagctgagat gaccttccgg aggcccgccc aggccttccc ggtcagctac
1800tcctcttccg gtgcccgccg gccctcgctg gactccatgg agaaccaggt ctccgtggat
1860gccttcaaga tcctggagga tccaaagtgg gaattccctc ggaagaactt ggttcttgga
1920aaaactctag gagaaggcga atttggaaaa gtggtcaagg caacggcctt ccatctgaaa
1980ggcagagcag ggtacaccac ggtggccgtg aagatgctga aagagaacgc ctccccgagt
2040gagctgcgag acctgctgtc agagttcaac gtcctgaagc aggtcaacca cccacatgtc
2100atcaaattgt atggggcctg cagccaggat ggcccgctcc tcctcatcgt ggagtacgcc
2160aaatacggct ccctgcgggg cttcctccgc gagagccgca aagtggggcc tggctacctg
2220ggcagtggag gcagccgcaa ctccagctcc ctggaccacc cggatgagcg ggccctcacc
2280atgggcgacc tcatctcatt tgcctggcag atctcacagg ggatgcagta tctggccgag
2340atgaagctcg ttcatcggga cttggcagcc agaaacatcc tggtagctga ggggcggaag
2400atgaagattt cggatttcgg cttgtcccga gatgtttatg aagaggattc ctacgtgaag
2460aggagccagg gtcggattcc agttaaatgg atggcaattg aatccctttt tgatcatatc
2520tacaccacgc aaagtgatgt atggtctttt ggtgtcctgc tgtgggagat cgtgacccta
2580gggggaaacc cctatcctgg gattcctcct gagcggctct tcaaccttct gaagaccggc
2640caccggatgg agaggccaga caactgcagc gaggagatgt accgcctgat gctgcaatgc
2700tggaagcagg agccggacaa aaggccggtg tttgcggaca tcagcaaaga cctggagaag
2760atgatggtta agaggagaga ctacttggac cttgcggcgt ccactccatc tgactccctg
2820atttatgacg acggcctctc agaggaggag acaccgctgg tggactgtaa taatgccccc
2880ctccctcgag ccctcccttc cacatggatt gaaaacaaac tctatggtag aatttcccat
2940gcatttacta gattctag
295815935PRTHomo sapiensmisc_featureKIF5B-RET (K15;R12 variant 4) 15Met
Ala Asp Leu Ala Glu Cys Asn Ile Lys Val Met Cys Arg Phe Arg 1
5 10 15 Pro Leu Asn Glu Ser Glu
Val Asn Arg Gly Asp Lys Tyr Ile Ala Lys 20
25 30 Phe Gln Gly Glu Asp Thr Val Val Ile Ala
Ser Lys Pro Tyr Ala Phe 35 40
45 Asp Arg Val Phe Gln Ser Ser Thr Ser Gln Glu Gln Val Tyr
Asn Asp 50 55 60
Cys Ala Lys Lys Ile Val Lys Asp Val Leu Glu Gly Tyr Asn Gly Thr 65
70 75 80 Ile Phe Ala Tyr Gly
Gln Thr Ser Ser Gly Lys Thr His Thr Met Glu 85
90 95 Gly Lys Leu His Asp Pro Glu Gly Met Gly
Ile Ile Pro Arg Ile Val 100 105
110 Gln Asp Ile Phe Asn Tyr Ile Tyr Ser Met Asp Glu Asn Leu Glu
Phe 115 120 125 His
Ile Lys Val Ser Tyr Phe Glu Ile Tyr Leu Asp Lys Ile Arg Asp 130
135 140 Leu Leu Asp Val Ser Lys
Thr Asn Leu Ser Val His Glu Asp Lys Asn 145 150
155 160 Arg Val Pro Tyr Val Lys Gly Cys Thr Glu Arg
Phe Val Cys Ser Pro 165 170
175 Asp Glu Val Met Asp Thr Ile Asp Glu Gly Lys Ser Asn Arg His Val
180 185 190 Ala Val
Thr Asn Met Asn Glu His Ser Ser Arg Ser His Ser Ile Phe 195
200 205 Leu Ile Asn Val Lys Gln Glu
Asn Thr Gln Thr Glu Gln Lys Leu Ser 210 215
220 Gly Lys Leu Tyr Leu Val Asp Leu Ala Gly Ser Glu
Lys Val Ser Lys 225 230 235
240 Thr Gly Ala Glu Gly Ala Val Leu Asp Glu Ala Lys Asn Ile Asn Lys
245 250 255 Ser Leu Ser
Ala Leu Gly Asn Val Ile Ser Ala Leu Ala Glu Gly Ser 260
265 270 Thr Tyr Val Pro Tyr Arg Asp Ser
Lys Met Thr Arg Ile Leu Gln Asp 275 280
285 Ser Leu Gly Gly Asn Cys Arg Thr Thr Ile Val Ile Cys
Cys Ser Pro 290 295 300
Ser Ser Tyr Asn Glu Ser Glu Thr Lys Ser Thr Leu Leu Phe Gly Gln 305
310 315 320 Arg Ala Lys Thr
Ile Lys Asn Thr Val Cys Val Asn Val Glu Leu Thr 325
330 335 Ala Glu Gln Trp Lys Lys Lys Tyr Glu
Lys Glu Lys Glu Lys Asn Lys 340 345
350 Ile Leu Arg Asn Thr Ile Gln Trp Leu Glu Asn Glu Leu Asn
Arg Trp 355 360 365
Arg Asn Gly Glu Thr Val Pro Ile Asp Glu Gln Phe Asp Lys Glu Lys 370
375 380 Ala Asn Leu Glu Ala
Phe Thr Val Asp Lys Asp Ile Thr Leu Thr Asn 385 390
395 400 Asp Lys Pro Ala Thr Ala Ile Gly Val Ile
Gly Asn Phe Thr Asp Ala 405 410
415 Glu Arg Arg Lys Cys Glu Glu Glu Ile Ala Lys Leu Tyr Lys Gln
Leu 420 425 430 Asp
Asp Lys Asp Glu Glu Ile Asn Gln Gln Ser Gln Leu Val Glu Lys 435
440 445 Leu Lys Thr Gln Met Leu
Asp Gln Glu Glu Leu Leu Ala Ser Thr Arg 450 455
460 Arg Asp Gln Asp Asn Met Gln Ala Glu Leu Asn
Arg Leu Gln Ala Glu 465 470 475
480 Asn Asp Ala Ser Lys Glu Glu Val Lys Glu Val Leu Gln Ala Leu Glu
485 490 495 Glu Leu
Ala Val Asn Tyr Asp Gln Lys Ser Gln Glu Val Glu Asp Lys 500
505 510 Thr Lys Glu Tyr Glu Leu Leu
Ser Asp Glu Leu Asn Gln Lys Ser Ala 515 520
525 Thr Leu Ala Ser Ile Asp Ala Glu Leu Gln Lys Leu
Lys Glu Met Thr 530 535 540
Asn His Gln Lys Lys Arg Ala Ala Glu Met Met Ala Ser Leu Leu Lys 545
550 555 560 Asp Leu Ala
Glu Ile Gly Ile Ala Val Gly Asn Asn Asp Val Lys Glu 565
570 575 Asp Pro Lys Trp Glu Phe Pro Arg
Lys Asn Leu Val Leu Gly Lys Thr 580 585
590 Leu Gly Glu Gly Glu Phe Gly Lys Val Val Lys Ala Thr
Ala Phe His 595 600 605
Leu Lys Gly Arg Ala Gly Tyr Thr Thr Val Ala Val Lys Met Leu Lys 610
615 620 Glu Asn Ala Ser
Pro Ser Glu Leu Arg Asp Leu Leu Ser Glu Phe Asn 625 630
635 640 Val Leu Lys Gln Val Asn His Pro His
Val Ile Lys Leu Tyr Gly Ala 645 650
655 Cys Ser Gln Asp Gly Pro Leu Leu Leu Ile Val Glu Tyr Ala
Lys Tyr 660 665 670
Gly Ser Leu Arg Gly Phe Leu Arg Glu Ser Arg Lys Val Gly Pro Gly
675 680 685 Tyr Leu Gly Ser
Gly Gly Ser Arg Asn Ser Ser Ser Leu Asp His Pro 690
695 700 Asp Glu Arg Ala Leu Thr Met Gly
Asp Leu Ile Ser Phe Ala Trp Gln 705 710
715 720 Ile Ser Gln Gly Met Gln Tyr Leu Ala Glu Met Lys
Leu Val His Arg 725 730
735 Asp Leu Ala Ala Arg Asn Ile Leu Val Ala Glu Gly Arg Lys Met Lys
740 745 750 Ile Ser Asp
Phe Gly Leu Ser Arg Asp Val Tyr Glu Glu Asp Ser Tyr 755
760 765 Val Lys Arg Ser Gln Gly Arg Ile
Pro Val Lys Trp Met Ala Ile Glu 770 775
780 Ser Leu Phe Asp His Ile Tyr Thr Thr Gln Ser Asp Val
Trp Ser Phe 785 790 795
800 Gly Val Leu Leu Trp Glu Ile Val Thr Leu Gly Gly Asn Pro Tyr Pro
805 810 815 Gly Ile Pro Pro
Glu Arg Leu Phe Asn Leu Leu Lys Thr Gly His Arg 820
825 830 Met Glu Arg Pro Asp Asn Cys Ser Glu
Glu Met Tyr Arg Leu Met Leu 835 840
845 Gln Cys Trp Lys Gln Glu Pro Asp Lys Arg Pro Val Phe Ala
Asp Ile 850 855 860
Ser Lys Asp Leu Glu Lys Met Met Val Lys Arg Arg Asp Tyr Leu Asp 865
870 875 880 Leu Ala Ala Ser Thr
Pro Ser Asp Ser Leu Ile Tyr Asp Asp Gly Leu 885
890 895 Ser Glu Glu Glu Thr Pro Leu Val Asp Cys
Asn Asn Ala Pro Leu Pro 900 905
910 Arg Ala Leu Pro Ser Thr Trp Ile Glu Asn Lys Leu Tyr Gly Arg
Ile 915 920 925 Ser
His Ala Phe Thr Arg Phe 930 935 16998PRTHomo
sapiensmisc_featureKIF5B-RET (K16;R12 variant4) 16Met Ala Asp Leu Ala Glu
Cys Asn Ile Lys Val Met Cys Arg Phe Arg 1 5
10 15 Pro Leu Asn Glu Ser Glu Val Asn Arg Gly Asp
Lys Tyr Ile Ala Lys 20 25
30 Phe Gln Gly Glu Asp Thr Val Val Ile Ala Ser Lys Pro Tyr Ala
Phe 35 40 45 Asp
Arg Val Phe Gln Ser Ser Thr Ser Gln Glu Gln Val Tyr Asn Asp 50
55 60 Cys Ala Lys Lys Ile Val
Lys Asp Val Leu Glu Gly Tyr Asn Gly Thr 65 70
75 80 Ile Phe Ala Tyr Gly Gln Thr Ser Ser Gly Lys
Thr His Thr Met Glu 85 90
95 Gly Lys Leu His Asp Pro Glu Gly Met Gly Ile Ile Pro Arg Ile Val
100 105 110 Gln Asp
Ile Phe Asn Tyr Ile Tyr Ser Met Asp Glu Asn Leu Glu Phe 115
120 125 His Ile Lys Val Ser Tyr Phe
Glu Ile Tyr Leu Asp Lys Ile Arg Asp 130 135
140 Leu Leu Asp Val Ser Lys Thr Asn Leu Ser Val His
Glu Asp Lys Asn 145 150 155
160 Arg Val Pro Tyr Val Lys Gly Cys Thr Glu Arg Phe Val Cys Ser Pro
165 170 175 Asp Glu Val
Met Asp Thr Ile Asp Glu Gly Lys Ser Asn Arg His Val 180
185 190 Ala Val Thr Asn Met Asn Glu His
Ser Ser Arg Ser His Ser Ile Phe 195 200
205 Leu Ile Asn Val Lys Gln Glu Asn Thr Gln Thr Glu Gln
Lys Leu Ser 210 215 220
Gly Lys Leu Tyr Leu Val Asp Leu Ala Gly Ser Glu Lys Val Ser Lys 225
230 235 240 Thr Gly Ala Glu
Gly Ala Val Leu Asp Glu Ala Lys Asn Ile Asn Lys 245
250 255 Ser Leu Ser Ala Leu Gly Asn Val Ile
Ser Ala Leu Ala Glu Gly Ser 260 265
270 Thr Tyr Val Pro Tyr Arg Asp Ser Lys Met Thr Arg Ile Leu
Gln Asp 275 280 285
Ser Leu Gly Gly Asn Cys Arg Thr Thr Ile Val Ile Cys Cys Ser Pro 290
295 300 Ser Ser Tyr Asn Glu
Ser Glu Thr Lys Ser Thr Leu Leu Phe Gly Gln 305 310
315 320 Arg Ala Lys Thr Ile Lys Asn Thr Val Cys
Val Asn Val Glu Leu Thr 325 330
335 Ala Glu Gln Trp Lys Lys Lys Tyr Glu Lys Glu Lys Glu Lys Asn
Lys 340 345 350 Ile
Leu Arg Asn Thr Ile Gln Trp Leu Glu Asn Glu Leu Asn Arg Trp 355
360 365 Arg Asn Gly Glu Thr Val
Pro Ile Asp Glu Gln Phe Asp Lys Glu Lys 370 375
380 Ala Asn Leu Glu Ala Phe Thr Val Asp Lys Asp
Ile Thr Leu Thr Asn 385 390 395
400 Asp Lys Pro Ala Thr Ala Ile Gly Val Ile Gly Asn Phe Thr Asp Ala
405 410 415 Glu Arg
Arg Lys Cys Glu Glu Glu Ile Ala Lys Leu Tyr Lys Gln Leu 420
425 430 Asp Asp Lys Asp Glu Glu Ile
Asn Gln Gln Ser Gln Leu Val Glu Lys 435 440
445 Leu Lys Thr Gln Met Leu Asp Gln Glu Glu Leu Leu
Ala Ser Thr Arg 450 455 460
Arg Asp Gln Asp Asn Met Gln Ala Glu Leu Asn Arg Leu Gln Ala Glu 465
470 475 480 Asn Asp Ala
Ser Lys Glu Glu Val Lys Glu Val Leu Gln Ala Leu Glu 485
490 495 Glu Leu Ala Val Asn Tyr Asp Gln
Lys Ser Gln Glu Val Glu Asp Lys 500 505
510 Thr Lys Glu Tyr Glu Leu Leu Ser Asp Glu Leu Asn Gln
Lys Ser Ala 515 520 525
Thr Leu Ala Ser Ile Asp Ala Glu Leu Gln Lys Leu Lys Glu Met Thr 530
535 540 Asn His Gln Lys
Lys Arg Ala Ala Glu Met Met Ala Ser Leu Leu Lys 545 550
555 560 Asp Leu Ala Glu Ile Gly Ile Ala Val
Gly Asn Asn Asp Val Lys Gln 565 570
575 Pro Glu Gly Thr Gly Met Ile Asp Glu Glu Phe Thr Val Ala
Arg Leu 580 585 590
Tyr Ile Ser Lys Met Lys Ser Glu Val Lys Thr Met Val Lys Arg Cys
595 600 605 Lys Gln Leu Glu
Ser Thr Gln Thr Glu Ser Asn Lys Lys Met Glu Glu 610
615 620 Asn Glu Lys Glu Leu Ala Ala Cys
Gln Leu Arg Ile Ser Gln Glu Asp 625 630
635 640 Pro Lys Trp Glu Phe Pro Arg Lys Asn Leu Val Leu
Gly Lys Thr Leu 645 650
655 Gly Glu Gly Glu Phe Gly Lys Val Val Lys Ala Thr Ala Phe His Leu
660 665 670 Lys Gly Arg
Ala Gly Tyr Thr Thr Val Ala Val Lys Met Leu Lys Glu 675
680 685 Asn Ala Ser Pro Ser Glu Leu Arg
Asp Leu Leu Ser Glu Phe Asn Val 690 695
700 Leu Lys Gln Val Asn His Pro His Val Ile Lys Leu Tyr
Gly Ala Cys 705 710 715
720 Ser Gln Asp Gly Pro Leu Leu Leu Ile Val Glu Tyr Ala Lys Tyr Gly
725 730 735 Ser Leu Arg Gly
Phe Leu Arg Glu Ser Arg Lys Val Gly Pro Gly Tyr 740
745 750 Leu Gly Ser Gly Gly Ser Arg Asn Ser
Ser Ser Leu Asp His Pro Asp 755 760
765 Glu Arg Ala Leu Thr Met Gly Asp Leu Ile Ser Phe Ala Trp
Gln Ile 770 775 780
Ser Gln Gly Met Gln Tyr Leu Ala Glu Met Lys Leu Val His Arg Asp 785
790 795 800 Leu Ala Ala Arg Asn
Ile Leu Val Ala Glu Gly Arg Lys Met Lys Ile 805
810 815 Ser Asp Phe Gly Leu Ser Arg Asp Val Tyr
Glu Glu Asp Ser Tyr Val 820 825
830 Lys Arg Ser Gln Gly Arg Ile Pro Val Lys Trp Met Ala Ile Glu
Ser 835 840 845 Leu
Phe Asp His Ile Tyr Thr Thr Gln Ser Asp Val Trp Ser Phe Gly 850
855 860 Val Leu Leu Trp Glu Ile
Val Thr Leu Gly Gly Asn Pro Tyr Pro Gly 865 870
875 880 Ile Pro Pro Glu Arg Leu Phe Asn Leu Leu Lys
Thr Gly His Arg Met 885 890
895 Glu Arg Pro Asp Asn Cys Ser Glu Glu Met Tyr Arg Leu Met Leu Gln
900 905 910 Cys Trp
Lys Gln Glu Pro Asp Lys Arg Pro Val Phe Ala Asp Ile Ser 915
920 925 Lys Asp Leu Glu Lys Met Met
Val Lys Arg Arg Asp Tyr Leu Asp Leu 930 935
940 Ala Ala Ser Thr Pro Ser Asp Ser Leu Ile Tyr Asp
Asp Gly Leu Ser 945 950 955
960 Glu Glu Glu Thr Pro Leu Val Asp Cys Asn Asn Ala Pro Leu Pro Arg
965 970 975 Ala Leu Pro
Ser Thr Trp Ile Glu Asn Lys Leu Tyr Gly Arg Ile Ser 980
985 990 His Ala Phe Thr Arg Phe
995 171173PRTHomo sapiensmisc_featureKIF5B-RET (K22;R12
variant4) 17Met Ala Asp Leu Ala Glu Cys Asn Ile Lys Val Met Cys Arg Phe
Arg 1 5 10 15 Pro
Leu Asn Glu Ser Glu Val Asn Arg Gly Asp Lys Tyr Ile Ala Lys
20 25 30 Phe Gln Gly Glu Asp
Thr Val Val Ile Ala Ser Lys Pro Tyr Ala Phe 35
40 45 Asp Arg Val Phe Gln Ser Ser Thr Ser
Gln Glu Gln Val Tyr Asn Asp 50 55
60 Cys Ala Lys Lys Ile Val Lys Asp Val Leu Glu Gly Tyr
Asn Gly Thr 65 70 75
80 Ile Phe Ala Tyr Gly Gln Thr Ser Ser Gly Lys Thr His Thr Met Glu
85 90 95 Gly Lys Leu His
Asp Pro Glu Gly Met Gly Ile Ile Pro Arg Ile Val 100
105 110 Gln Asp Ile Phe Asn Tyr Ile Tyr Ser
Met Asp Glu Asn Leu Glu Phe 115 120
125 His Ile Lys Val Ser Tyr Phe Glu Ile Tyr Leu Asp Lys Ile
Arg Asp 130 135 140
Leu Leu Asp Val Ser Lys Thr Asn Leu Ser Val His Glu Asp Lys Asn 145
150 155 160 Arg Val Pro Tyr Val
Lys Gly Cys Thr Glu Arg Phe Val Cys Ser Pro 165
170 175 Asp Glu Val Met Asp Thr Ile Asp Glu Gly
Lys Ser Asn Arg His Val 180 185
190 Ala Val Thr Asn Met Asn Glu His Ser Ser Arg Ser His Ser Ile
Phe 195 200 205 Leu
Ile Asn Val Lys Gln Glu Asn Thr Gln Thr Glu Gln Lys Leu Ser 210
215 220 Gly Lys Leu Tyr Leu Val
Asp Leu Ala Gly Ser Glu Lys Val Ser Lys 225 230
235 240 Thr Gly Ala Glu Gly Ala Val Leu Asp Glu Ala
Lys Asn Ile Asn Lys 245 250
255 Ser Leu Ser Ala Leu Gly Asn Val Ile Ser Ala Leu Ala Glu Gly Ser
260 265 270 Thr Tyr
Val Pro Tyr Arg Asp Ser Lys Met Thr Arg Ile Leu Gln Asp 275
280 285 Ser Leu Gly Gly Asn Cys Arg
Thr Thr Ile Val Ile Cys Cys Ser Pro 290 295
300 Ser Ser Tyr Asn Glu Ser Glu Thr Lys Ser Thr Leu
Leu Phe Gly Gln 305 310 315
320 Arg Ala Lys Thr Ile Lys Asn Thr Val Cys Val Asn Val Glu Leu Thr
325 330 335 Ala Glu Gln
Trp Lys Lys Lys Tyr Glu Lys Glu Lys Glu Lys Asn Lys 340
345 350 Ile Leu Arg Asn Thr Ile Gln Trp
Leu Glu Asn Glu Leu Asn Arg Trp 355 360
365 Arg Asn Gly Glu Thr Val Pro Ile Asp Glu Gln Phe Asp
Lys Glu Lys 370 375 380
Ala Asn Leu Glu Ala Phe Thr Val Asp Lys Asp Ile Thr Leu Thr Asn 385
390 395 400 Asp Lys Pro Ala
Thr Ala Ile Gly Val Ile Gly Asn Phe Thr Asp Ala 405
410 415 Glu Arg Arg Lys Cys Glu Glu Glu Ile
Ala Lys Leu Tyr Lys Gln Leu 420 425
430 Asp Asp Lys Asp Glu Glu Ile Asn Gln Gln Ser Gln Leu Val
Glu Lys 435 440 445
Leu Lys Thr Gln Met Leu Asp Gln Glu Glu Leu Leu Ala Ser Thr Arg 450
455 460 Arg Asp Gln Asp Asn
Met Gln Ala Glu Leu Asn Arg Leu Gln Ala Glu 465 470
475 480 Asn Asp Ala Ser Lys Glu Glu Val Lys Glu
Val Leu Gln Ala Leu Glu 485 490
495 Glu Leu Ala Val Asn Tyr Asp Gln Lys Ser Gln Glu Val Glu Asp
Lys 500 505 510 Thr
Lys Glu Tyr Glu Leu Leu Ser Asp Glu Leu Asn Gln Lys Ser Ala 515
520 525 Thr Leu Ala Ser Ile Asp
Ala Glu Leu Gln Lys Leu Lys Glu Met Thr 530 535
540 Asn His Gln Lys Lys Arg Ala Ala Glu Met Met
Ala Ser Leu Leu Lys 545 550 555
560 Asp Leu Ala Glu Ile Gly Ile Ala Val Gly Asn Asn Asp Val Lys Gln
565 570 575 Pro Glu
Gly Thr Gly Met Ile Asp Glu Glu Phe Thr Val Ala Arg Leu 580
585 590 Tyr Ile Ser Lys Met Lys Ser
Glu Val Lys Thr Met Val Lys Arg Cys 595 600
605 Lys Gln Leu Glu Ser Thr Gln Thr Glu Ser Asn Lys
Lys Met Glu Glu 610 615 620
Asn Glu Lys Glu Leu Ala Ala Cys Gln Leu Arg Ile Ser Gln His Glu 625
630 635 640 Ala Lys Ile
Lys Ser Leu Thr Glu Tyr Leu Gln Asn Val Glu Gln Lys 645
650 655 Lys Arg Gln Leu Glu Glu Ser Val
Asp Ala Leu Ser Glu Glu Leu Val 660 665
670 Gln Leu Arg Ala Gln Glu Lys Val His Glu Met Glu Lys
Glu His Leu 675 680 685
Asn Lys Val Gln Thr Ala Asn Glu Val Lys Gln Ala Val Glu Gln Gln 690
695 700 Ile Gln Ser His
Arg Glu Thr His Gln Lys Gln Ile Ser Ser Leu Arg 705 710
715 720 Asp Glu Val Glu Ala Lys Ala Lys Leu
Ile Thr Asp Leu Gln Asp Gln 725 730
735 Asn Gln Lys Met Met Leu Glu Gln Glu Arg Leu Arg Val Glu
His Glu 740 745 750
Lys Leu Lys Ala Thr Asp Gln Glu Lys Ser Arg Lys Leu His Glu Leu
755 760 765 Thr Val Met Gln
Asp Arg Arg Glu Gln Ala Arg Gln Asp Leu Lys Gly 770
775 780 Leu Glu Glu Thr Val Ala Lys Glu
Leu Gln Thr Leu His Asn Leu Arg 785 790
795 800 Lys Leu Phe Val Gln Asp Leu Ala Thr Arg Val Lys
Lys Glu Asp Pro 805 810
815 Lys Trp Glu Phe Pro Arg Lys Asn Leu Val Leu Gly Lys Thr Leu Gly
820 825 830 Glu Gly Glu
Phe Gly Lys Val Val Lys Ala Thr Ala Phe His Leu Lys 835
840 845 Gly Arg Ala Gly Tyr Thr Thr Val
Ala Val Lys Met Leu Lys Glu Asn 850 855
860 Ala Ser Pro Ser Glu Leu Arg Asp Leu Leu Ser Glu Phe
Asn Val Leu 865 870 875
880 Lys Gln Val Asn His Pro His Val Ile Lys Leu Tyr Gly Ala Cys Ser
885 890 895 Gln Asp Gly Pro
Leu Leu Leu Ile Val Glu Tyr Ala Lys Tyr Gly Ser 900
905 910 Leu Arg Gly Phe Leu Arg Glu Ser Arg
Lys Val Gly Pro Gly Tyr Leu 915 920
925 Gly Ser Gly Gly Ser Arg Asn Ser Ser Ser Leu Asp His Pro
Asp Glu 930 935 940
Arg Ala Leu Thr Met Gly Asp Leu Ile Ser Phe Ala Trp Gln Ile Ser 945
950 955 960 Gln Gly Met Gln Tyr
Leu Ala Glu Met Lys Leu Val His Arg Asp Leu 965
970 975 Ala Ala Arg Asn Ile Leu Val Ala Glu Gly
Arg Lys Met Lys Ile Ser 980 985
990 Asp Phe Gly Leu Ser Arg Asp Val Tyr Glu Glu Asp Ser Tyr
Val Lys 995 1000 1005
Arg Ser Gln Gly Arg Ile Pro Val Lys Trp Met Ala Ile Glu Ser 1010
1015 1020 Leu Phe Asp His Ile
Tyr Thr Thr Gln Ser Asp Val Trp Ser Phe 1025 1030
1035 Gly Val Leu Leu Trp Glu Ile Val Thr Leu
Gly Gly Asn Pro Tyr 1040 1045 1050
Pro Gly Ile Pro Pro Glu Arg Leu Phe Asn Leu Leu Lys Thr Gly
1055 1060 1065 His Arg
Met Glu Arg Pro Asp Asn Cys Ser Glu Glu Met Tyr Arg 1070
1075 1080 Leu Met Leu Gln Cys Trp Lys
Gln Glu Pro Asp Lys Arg Pro Val 1085 1090
1095 Phe Ala Asp Ile Ser Lys Asp Leu Glu Lys Met Met
Val Lys Arg 1100 1105 1110
Arg Asp Tyr Leu Asp Leu Ala Ala Ser Thr Pro Ser Asp Ser Leu 1115
1120 1125 Ile Tyr Asp Asp Gly
Leu Ser Glu Glu Glu Thr Pro Leu Val Asp 1130 1135
1140 Cys Asn Asn Ala Pro Leu Pro Arg Ala Leu
Pro Ser Thr Trp Ile 1145 1150 1155
Glu Asn Lys Leu Tyr Gly Arg Ile Ser His Ala Phe Thr Arg Phe
1160 1165 1170
181208PRTHomo sapiensmisc_featureKIF5B-RET (K23;R12 variant4) 18Met Ala
Asp Leu Ala Glu Cys Asn Ile Lys Val Met Cys Arg Phe Arg 1 5
10 15 Pro Leu Asn Glu Ser Glu Val
Asn Arg Gly Asp Lys Tyr Ile Ala Lys 20 25
30 Phe Gln Gly Glu Asp Thr Val Val Ile Ala Ser Lys
Pro Tyr Ala Phe 35 40 45
Asp Arg Val Phe Gln Ser Ser Thr Ser Gln Glu Gln Val Tyr Asn Asp
50 55 60 Cys Ala Lys
Lys Ile Val Lys Asp Val Leu Glu Gly Tyr Asn Gly Thr 65
70 75 80 Ile Phe Ala Tyr Gly Gln Thr
Ser Ser Gly Lys Thr His Thr Met Glu 85
90 95 Gly Lys Leu His Asp Pro Glu Gly Met Gly Ile
Ile Pro Arg Ile Val 100 105
110 Gln Asp Ile Phe Asn Tyr Ile Tyr Ser Met Asp Glu Asn Leu Glu
Phe 115 120 125 His
Ile Lys Val Ser Tyr Phe Glu Ile Tyr Leu Asp Lys Ile Arg Asp 130
135 140 Leu Leu Asp Val Ser Lys
Thr Asn Leu Ser Val His Glu Asp Lys Asn 145 150
155 160 Arg Val Pro Tyr Val Lys Gly Cys Thr Glu Arg
Phe Val Cys Ser Pro 165 170
175 Asp Glu Val Met Asp Thr Ile Asp Glu Gly Lys Ser Asn Arg His Val
180 185 190 Ala Val
Thr Asn Met Asn Glu His Ser Ser Arg Ser His Ser Ile Phe 195
200 205 Leu Ile Asn Val Lys Gln Glu
Asn Thr Gln Thr Glu Gln Lys Leu Ser 210 215
220 Gly Lys Leu Tyr Leu Val Asp Leu Ala Gly Ser Glu
Lys Val Ser Lys 225 230 235
240 Thr Gly Ala Glu Gly Ala Val Leu Asp Glu Ala Lys Asn Ile Asn Lys
245 250 255 Ser Leu Ser
Ala Leu Gly Asn Val Ile Ser Ala Leu Ala Glu Gly Ser 260
265 270 Thr Tyr Val Pro Tyr Arg Asp Ser
Lys Met Thr Arg Ile Leu Gln Asp 275 280
285 Ser Leu Gly Gly Asn Cys Arg Thr Thr Ile Val Ile Cys
Cys Ser Pro 290 295 300
Ser Ser Tyr Asn Glu Ser Glu Thr Lys Ser Thr Leu Leu Phe Gly Gln 305
310 315 320 Arg Ala Lys Thr
Ile Lys Asn Thr Val Cys Val Asn Val Glu Leu Thr 325
330 335 Ala Glu Gln Trp Lys Lys Lys Tyr Glu
Lys Glu Lys Glu Lys Asn Lys 340 345
350 Ile Leu Arg Asn Thr Ile Gln Trp Leu Glu Asn Glu Leu Asn
Arg Trp 355 360 365
Arg Asn Gly Glu Thr Val Pro Ile Asp Glu Gln Phe Asp Lys Glu Lys 370
375 380 Ala Asn Leu Glu Ala
Phe Thr Val Asp Lys Asp Ile Thr Leu Thr Asn 385 390
395 400 Asp Lys Pro Ala Thr Ala Ile Gly Val Ile
Gly Asn Phe Thr Asp Ala 405 410
415 Glu Arg Arg Lys Cys Glu Glu Glu Ile Ala Lys Leu Tyr Lys Gln
Leu 420 425 430 Asp
Asp Lys Asp Glu Glu Ile Asn Gln Gln Ser Gln Leu Val Glu Lys 435
440 445 Leu Lys Thr Gln Met Leu
Asp Gln Glu Glu Leu Leu Ala Ser Thr Arg 450 455
460 Arg Asp Gln Asp Asn Met Gln Ala Glu Leu Asn
Arg Leu Gln Ala Glu 465 470 475
480 Asn Asp Ala Ser Lys Glu Glu Val Lys Glu Val Leu Gln Ala Leu Glu
485 490 495 Glu Leu
Ala Val Asn Tyr Asp Gln Lys Ser Gln Glu Val Glu Asp Lys 500
505 510 Thr Lys Glu Tyr Glu Leu Leu
Ser Asp Glu Leu Asn Gln Lys Ser Ala 515 520
525 Thr Leu Ala Ser Ile Asp Ala Glu Leu Gln Lys Leu
Lys Glu Met Thr 530 535 540
Asn His Gln Lys Lys Arg Ala Ala Glu Met Met Ala Ser Leu Leu Lys 545
550 555 560 Asp Leu Ala
Glu Ile Gly Ile Ala Val Gly Asn Asn Asp Val Lys Gln 565
570 575 Pro Glu Gly Thr Gly Met Ile Asp
Glu Glu Phe Thr Val Ala Arg Leu 580 585
590 Tyr Ile Ser Lys Met Lys Ser Glu Val Lys Thr Met Val
Lys Arg Cys 595 600 605
Lys Gln Leu Glu Ser Thr Gln Thr Glu Ser Asn Lys Lys Met Glu Glu 610
615 620 Asn Glu Lys Glu
Leu Ala Ala Cys Gln Leu Arg Ile Ser Gln His Glu 625 630
635 640 Ala Lys Ile Lys Ser Leu Thr Glu Tyr
Leu Gln Asn Val Glu Gln Lys 645 650
655 Lys Arg Gln Leu Glu Glu Ser Val Asp Ala Leu Ser Glu Glu
Leu Val 660 665 670
Gln Leu Arg Ala Gln Glu Lys Val His Glu Met Glu Lys Glu His Leu
675 680 685 Asn Lys Val Gln
Thr Ala Asn Glu Val Lys Gln Ala Val Glu Gln Gln 690
695 700 Ile Gln Ser His Arg Glu Thr His
Gln Lys Gln Ile Ser Ser Leu Arg 705 710
715 720 Asp Glu Val Glu Ala Lys Ala Lys Leu Ile Thr Asp
Leu Gln Asp Gln 725 730
735 Asn Gln Lys Met Met Leu Glu Gln Glu Arg Leu Arg Val Glu His Glu
740 745 750 Lys Leu Lys
Ala Thr Asp Gln Glu Lys Ser Arg Lys Leu His Glu Leu 755
760 765 Thr Val Met Gln Asp Arg Arg Glu
Gln Ala Arg Gln Asp Leu Lys Gly 770 775
780 Leu Glu Glu Thr Val Ala Lys Glu Leu Gln Thr Leu His
Asn Leu Arg 785 790 795
800 Lys Leu Phe Val Gln Asp Leu Ala Thr Arg Val Lys Lys Ser Ala Glu
805 810 815 Ile Asp Ser Asp
Asp Thr Gly Gly Ser Ala Ala Gln Lys Gln Lys Ile 820
825 830 Ser Phe Leu Glu Asn Asn Leu Glu Gln
Leu Thr Lys Val His Lys Gln 835 840
845 Glu Asp Pro Lys Trp Glu Phe Pro Arg Lys Asn Leu Val Leu
Gly Lys 850 855 860
Thr Leu Gly Glu Gly Glu Phe Gly Lys Val Val Lys Ala Thr Ala Phe 865
870 875 880 His Leu Lys Gly Arg
Ala Gly Tyr Thr Thr Val Ala Val Lys Met Leu 885
890 895 Lys Glu Asn Ala Ser Pro Ser Glu Leu Arg
Asp Leu Leu Ser Glu Phe 900 905
910 Asn Val Leu Lys Gln Val Asn His Pro His Val Ile Lys Leu Tyr
Gly 915 920 925 Ala
Cys Ser Gln Asp Gly Pro Leu Leu Leu Ile Val Glu Tyr Ala Lys 930
935 940 Tyr Gly Ser Leu Arg Gly
Phe Leu Arg Glu Ser Arg Lys Val Gly Pro 945 950
955 960 Gly Tyr Leu Gly Ser Gly Gly Ser Arg Asn Ser
Ser Ser Leu Asp His 965 970
975 Pro Asp Glu Arg Ala Leu Thr Met Gly Asp Leu Ile Ser Phe Ala Trp
980 985 990 Gln Ile
Ser Gln Gly Met Gln Tyr Leu Ala Glu Met Lys Leu Val His 995
1000 1005 Arg Asp Leu Ala Ala
Arg Asn Ile Leu Val Ala Glu Gly Arg Lys 1010 1015
1020 Met Lys Ile Ser Asp Phe Gly Leu Ser Arg
Asp Val Tyr Glu Glu 1025 1030 1035
Asp Ser Tyr Val Lys Arg Ser Gln Gly Arg Ile Pro Val Lys Trp
1040 1045 1050 Met Ala
Ile Glu Ser Leu Phe Asp His Ile Tyr Thr Thr Gln Ser 1055
1060 1065 Asp Val Trp Ser Phe Gly Val
Leu Leu Trp Glu Ile Val Thr Leu 1070 1075
1080 Gly Gly Asn Pro Tyr Pro Gly Ile Pro Pro Glu Arg
Leu Phe Asn 1085 1090 1095
Leu Leu Lys Thr Gly His Arg Met Glu Arg Pro Asp Asn Cys Ser 1100
1105 1110 Glu Glu Met Tyr Arg
Leu Met Leu Gln Cys Trp Lys Gln Glu Pro 1115 1120
1125 Asp Lys Arg Pro Val Phe Ala Asp Ile Ser
Lys Asp Leu Glu Lys 1130 1135 1140
Met Met Val Lys Arg Arg Asp Tyr Leu Asp Leu Ala Ala Ser Thr
1145 1150 1155 Pro Ser
Asp Ser Leu Ile Tyr Asp Asp Gly Leu Ser Glu Glu Glu 1160
1165 1170 Thr Pro Leu Val Asp Cys Asn
Asn Ala Pro Leu Pro Arg Ala Leu 1175 1180
1185 Pro Ser Thr Trp Ile Glu Asn Lys Leu Tyr Gly Arg
Ile Ser His 1190 1195 1200
Ala Phe Thr Arg Phe 1205 191366PRTHomo
sapiensmisc_featureKIF5B-RET (K24;R11 variant4) 19Met Ala Asp Leu Ala Glu
Cys Asn Ile Lys Val Met Cys Arg Phe Arg 1 5
10 15 Pro Leu Asn Glu Ser Glu Val Asn Arg Gly Asp
Lys Tyr Ile Ala Lys 20 25
30 Phe Gln Gly Glu Asp Thr Val Val Ile Ala Ser Lys Pro Tyr Ala
Phe 35 40 45 Asp
Arg Val Phe Gln Ser Ser Thr Ser Gln Glu Gln Val Tyr Asn Asp 50
55 60 Cys Ala Lys Lys Ile Val
Lys Asp Val Leu Glu Gly Tyr Asn Gly Thr 65 70
75 80 Ile Phe Ala Tyr Gly Gln Thr Ser Ser Gly Lys
Thr His Thr Met Glu 85 90
95 Gly Lys Leu His Asp Pro Glu Gly Met Gly Ile Ile Pro Arg Ile Val
100 105 110 Gln Asp
Ile Phe Asn Tyr Ile Tyr Ser Met Asp Glu Asn Leu Glu Phe 115
120 125 His Ile Lys Val Ser Tyr Phe
Glu Ile Tyr Leu Asp Lys Ile Arg Asp 130 135
140 Leu Leu Asp Val Ser Lys Thr Asn Leu Ser Val His
Glu Asp Lys Asn 145 150 155
160 Arg Val Pro Tyr Val Lys Gly Cys Thr Glu Arg Phe Val Cys Ser Pro
165 170 175 Asp Glu Val
Met Asp Thr Ile Asp Glu Gly Lys Ser Asn Arg His Val 180
185 190 Ala Val Thr Asn Met Asn Glu His
Ser Ser Arg Ser His Ser Ile Phe 195 200
205 Leu Ile Asn Val Lys Gln Glu Asn Thr Gln Thr Glu Gln
Lys Leu Ser 210 215 220
Gly Lys Leu Tyr Leu Val Asp Leu Ala Gly Ser Glu Lys Val Ser Lys 225
230 235 240 Thr Gly Ala Glu
Gly Ala Val Leu Asp Glu Ala Lys Asn Ile Asn Lys 245
250 255 Ser Leu Ser Ala Leu Gly Asn Val Ile
Ser Ala Leu Ala Glu Gly Ser 260 265
270 Thr Tyr Val Pro Tyr Arg Asp Ser Lys Met Thr Arg Ile Leu
Gln Asp 275 280 285
Ser Leu Gly Gly Asn Cys Arg Thr Thr Ile Val Ile Cys Cys Ser Pro 290
295 300 Ser Ser Tyr Asn Glu
Ser Glu Thr Lys Ser Thr Leu Leu Phe Gly Gln 305 310
315 320 Arg Ala Lys Thr Ile Lys Asn Thr Val Cys
Val Asn Val Glu Leu Thr 325 330
335 Ala Glu Gln Trp Lys Lys Lys Tyr Glu Lys Glu Lys Glu Lys Asn
Lys 340 345 350 Ile
Leu Arg Asn Thr Ile Gln Trp Leu Glu Asn Glu Leu Asn Arg Trp 355
360 365 Arg Asn Gly Glu Thr Val
Pro Ile Asp Glu Gln Phe Asp Lys Glu Lys 370 375
380 Ala Asn Leu Glu Ala Phe Thr Val Asp Lys Asp
Ile Thr Leu Thr Asn 385 390 395
400 Asp Lys Pro Ala Thr Ala Ile Gly Val Ile Gly Asn Phe Thr Asp Ala
405 410 415 Glu Arg
Arg Lys Cys Glu Glu Glu Ile Ala Lys Leu Tyr Lys Gln Leu 420
425 430 Asp Asp Lys Asp Glu Glu Ile
Asn Gln Gln Ser Gln Leu Val Glu Lys 435 440
445 Leu Lys Thr Gln Met Leu Asp Gln Glu Glu Leu Leu
Ala Ser Thr Arg 450 455 460
Arg Asp Gln Asp Asn Met Gln Ala Glu Leu Asn Arg Leu Gln Ala Glu 465
470 475 480 Asn Asp Ala
Ser Lys Glu Glu Val Lys Glu Val Leu Gln Ala Leu Glu 485
490 495 Glu Leu Ala Val Asn Tyr Asp Gln
Lys Ser Gln Glu Val Glu Asp Lys 500 505
510 Thr Lys Glu Tyr Glu Leu Leu Ser Asp Glu Leu Asn Gln
Lys Ser Ala 515 520 525
Thr Leu Ala Ser Ile Asp Ala Glu Leu Gln Lys Leu Lys Glu Met Thr 530
535 540 Asn His Gln Lys
Lys Arg Ala Ala Glu Met Met Ala Ser Leu Leu Lys 545 550
555 560 Asp Leu Ala Glu Ile Gly Ile Ala Val
Gly Asn Asn Asp Val Lys Gln 565 570
575 Pro Glu Gly Thr Gly Met Ile Asp Glu Glu Phe Thr Val Ala
Arg Leu 580 585 590
Tyr Ile Ser Lys Met Lys Ser Glu Val Lys Thr Met Val Lys Arg Cys
595 600 605 Lys Gln Leu Glu
Ser Thr Gln Thr Glu Ser Asn Lys Lys Met Glu Glu 610
615 620 Asn Glu Lys Glu Leu Ala Ala Cys
Gln Leu Arg Ile Ser Gln His Glu 625 630
635 640 Ala Lys Ile Lys Ser Leu Thr Glu Tyr Leu Gln Asn
Val Glu Gln Lys 645 650
655 Lys Arg Gln Leu Glu Glu Ser Val Asp Ala Leu Ser Glu Glu Leu Val
660 665 670 Gln Leu Arg
Ala Gln Glu Lys Val His Glu Met Glu Lys Glu His Leu 675
680 685 Asn Lys Val Gln Thr Ala Asn Glu
Val Lys Gln Ala Val Glu Gln Gln 690 695
700 Ile Gln Ser His Arg Glu Thr His Gln Lys Gln Ile Ser
Ser Leu Arg 705 710 715
720 Asp Glu Val Glu Ala Lys Ala Lys Leu Ile Thr Asp Leu Gln Asp Gln
725 730 735 Asn Gln Lys Met
Met Leu Glu Gln Glu Arg Leu Arg Val Glu His Glu 740
745 750 Lys Leu Lys Ala Thr Asp Gln Glu Lys
Ser Arg Lys Leu His Glu Leu 755 760
765 Thr Val Met Gln Asp Arg Arg Glu Gln Ala Arg Gln Asp Leu
Lys Gly 770 775 780
Leu Glu Glu Thr Val Ala Lys Glu Leu Gln Thr Leu His Asn Leu Arg 785
790 795 800 Lys Leu Phe Val Gln
Asp Leu Ala Thr Arg Val Lys Lys Ser Ala Glu 805
810 815 Ile Asp Ser Asp Asp Thr Gly Gly Ser Ala
Ala Gln Lys Gln Lys Ile 820 825
830 Ser Phe Leu Glu Asn Asn Leu Glu Gln Leu Thr Lys Val His Lys
Gln 835 840 845 Leu
Val Arg Asp Asn Ala Asp Leu Arg Cys Glu Leu Pro Lys Leu Glu 850
855 860 Lys Arg Leu Arg Ala Thr
Ala Glu Arg Val Lys Ala Leu Glu Ser Ala 865 870
875 880 Leu Lys Glu Ala Lys Glu Asn Ala Ser Arg Asp
Arg Lys Arg Tyr Gln 885 890
895 Gln Glu Val Asp Arg Ile Lys Glu Ala Val Arg Ser Lys Asn Met Ala
900 905 910 Arg Arg
Gly His Ser Ala Gln Ile Asp Pro Leu Cys Asp Glu Leu Cys 915
920 925 Arg Thr Val Ile Ala Ala Ala
Val Leu Phe Ser Phe Ile Val Ser Val 930 935
940 Leu Leu Ser Ala Phe Cys Ile His Cys Tyr His Lys
Phe Ala His Lys 945 950 955
960 Pro Pro Ile Ser Ser Ala Glu Met Thr Phe Arg Arg Pro Ala Gln Ala
965 970 975 Phe Pro Val
Ser Tyr Ser Ser Ser Gly Ala Arg Arg Pro Ser Leu Asp 980
985 990 Ser Met Glu Asn Gln Val Ser Val
Asp Ala Phe Lys Ile Leu Glu Asp 995 1000
1005 Pro Lys Trp Glu Phe Pro Arg Lys Asn Leu Val
Leu Gly Lys Thr 1010 1015 1020
Leu Gly Glu Gly Glu Phe Gly Lys Val Val Lys Ala Thr Ala Phe
1025 1030 1035 His Leu Lys
Gly Arg Ala Gly Tyr Thr Thr Val Ala Val Lys Met 1040
1045 1050 Leu Lys Glu Asn Ala Ser Pro Ser
Glu Leu Arg Asp Leu Leu Ser 1055 1060
1065 Glu Phe Asn Val Leu Lys Gln Val Asn His Pro His Val
Ile Lys 1070 1075 1080
Leu Tyr Gly Ala Cys Ser Gln Asp Gly Pro Leu Leu Leu Ile Val 1085
1090 1095 Glu Tyr Ala Lys Tyr
Gly Ser Leu Arg Gly Phe Leu Arg Glu Ser 1100 1105
1110 Arg Lys Val Gly Pro Gly Tyr Leu Gly Ser
Gly Gly Ser Arg Asn 1115 1120 1125
Ser Ser Ser Leu Asp His Pro Asp Glu Arg Ala Leu Thr Met Gly
1130 1135 1140 Asp Leu
Ile Ser Phe Ala Trp Gln Ile Ser Gln Gly Met Gln Tyr 1145
1150 1155 Leu Ala Glu Met Lys Leu Val
His Arg Asp Leu Ala Ala Arg Asn 1160 1165
1170 Ile Leu Val Ala Glu Gly Arg Lys Met Lys Ile Ser
Asp Phe Gly 1175 1180 1185
Leu Ser Arg Asp Val Tyr Glu Glu Asp Ser Tyr Val Lys Arg Ser 1190
1195 1200 Gln Gly Arg Ile Pro
Val Lys Trp Met Ala Ile Glu Ser Leu Phe 1205 1210
1215 Asp His Ile Tyr Thr Thr Gln Ser Asp Val
Trp Ser Phe Gly Val 1220 1225 1230
Leu Leu Trp Glu Ile Val Thr Leu Gly Gly Asn Pro Tyr Pro Gly
1235 1240 1245 Ile Pro
Pro Glu Arg Leu Phe Asn Leu Leu Lys Thr Gly His Arg 1250
1255 1260 Met Glu Arg Pro Asp Asn Cys
Ser Glu Glu Met Tyr Arg Leu Met 1265 1270
1275 Leu Gln Cys Trp Lys Gln Glu Pro Asp Lys Arg Pro
Val Phe Ala 1280 1285 1290
Asp Ile Ser Lys Asp Leu Glu Lys Met Met Val Lys Arg Arg Asp 1295
1300 1305 Tyr Leu Asp Leu Ala
Ala Ser Thr Pro Ser Asp Ser Leu Ile Tyr 1310 1315
1320 Asp Asp Gly Leu Ser Glu Glu Glu Thr Pro
Leu Val Asp Cys Asn 1325 1330 1335
Asn Ala Pro Leu Pro Arg Ala Leu Pro Ser Thr Trp Ile Glu Asn
1340 1345 1350 Lys Leu
Tyr Gly Arg Ile Ser His Ala Phe Thr Arg Phe 1355
1360 1365 20977PRTHomo sapiensmisc_featureKIF5B-RET
(K15;R12 variant2) 20Met Ala Asp Leu Ala Glu Cys Asn Ile Lys Val Met Cys
Arg Phe Arg 1 5 10 15
Pro Leu Asn Glu Ser Glu Val Asn Arg Gly Asp Lys Tyr Ile Ala Lys
20 25 30 Phe Gln Gly Glu
Asp Thr Val Val Ile Ala Ser Lys Pro Tyr Ala Phe 35
40 45 Asp Arg Val Phe Gln Ser Ser Thr Ser
Gln Glu Gln Val Tyr Asn Asp 50 55
60 Cys Ala Lys Lys Ile Val Lys Asp Val Leu Glu Gly Tyr
Asn Gly Thr 65 70 75
80 Ile Phe Ala Tyr Gly Gln Thr Ser Ser Gly Lys Thr His Thr Met Glu
85 90 95 Gly Lys Leu His
Asp Pro Glu Gly Met Gly Ile Ile Pro Arg Ile Val 100
105 110 Gln Asp Ile Phe Asn Tyr Ile Tyr Ser
Met Asp Glu Asn Leu Glu Phe 115 120
125 His Ile Lys Val Ser Tyr Phe Glu Ile Tyr Leu Asp Lys Ile
Arg Asp 130 135 140
Leu Leu Asp Val Ser Lys Thr Asn Leu Ser Val His Glu Asp Lys Asn 145
150 155 160 Arg Val Pro Tyr Val
Lys Gly Cys Thr Glu Arg Phe Val Cys Ser Pro 165
170 175 Asp Glu Val Met Asp Thr Ile Asp Glu Gly
Lys Ser Asn Arg His Val 180 185
190 Ala Val Thr Asn Met Asn Glu His Ser Ser Arg Ser His Ser Ile
Phe 195 200 205 Leu
Ile Asn Val Lys Gln Glu Asn Thr Gln Thr Glu Gln Lys Leu Ser 210
215 220 Gly Lys Leu Tyr Leu Val
Asp Leu Ala Gly Ser Glu Lys Val Ser Lys 225 230
235 240 Thr Gly Ala Glu Gly Ala Val Leu Asp Glu Ala
Lys Asn Ile Asn Lys 245 250
255 Ser Leu Ser Ala Leu Gly Asn Val Ile Ser Ala Leu Ala Glu Gly Ser
260 265 270 Thr Tyr
Val Pro Tyr Arg Asp Ser Lys Met Thr Arg Ile Leu Gln Asp 275
280 285 Ser Leu Gly Gly Asn Cys Arg
Thr Thr Ile Val Ile Cys Cys Ser Pro 290 295
300 Ser Ser Tyr Asn Glu Ser Glu Thr Lys Ser Thr Leu
Leu Phe Gly Gln 305 310 315
320 Arg Ala Lys Thr Ile Lys Asn Thr Val Cys Val Asn Val Glu Leu Thr
325 330 335 Ala Glu Gln
Trp Lys Lys Lys Tyr Glu Lys Glu Lys Glu Lys Asn Lys 340
345 350 Ile Leu Arg Asn Thr Ile Gln Trp
Leu Glu Asn Glu Leu Asn Arg Trp 355 360
365 Arg Asn Gly Glu Thr Val Pro Ile Asp Glu Gln Phe Asp
Lys Glu Lys 370 375 380
Ala Asn Leu Glu Ala Phe Thr Val Asp Lys Asp Ile Thr Leu Thr Asn 385
390 395 400 Asp Lys Pro Ala
Thr Ala Ile Gly Val Ile Gly Asn Phe Thr Asp Ala 405
410 415 Glu Arg Arg Lys Cys Glu Glu Glu Ile
Ala Lys Leu Tyr Lys Gln Leu 420 425
430 Asp Asp Lys Asp Glu Glu Ile Asn Gln Gln Ser Gln Leu Val
Glu Lys 435 440 445
Leu Lys Thr Gln Met Leu Asp Gln Glu Glu Leu Leu Ala Ser Thr Arg 450
455 460 Arg Asp Gln Asp Asn
Met Gln Ala Glu Leu Asn Arg Leu Gln Ala Glu 465 470
475 480 Asn Asp Ala Ser Lys Glu Glu Val Lys Glu
Val Leu Gln Ala Leu Glu 485 490
495 Glu Leu Ala Val Asn Tyr Asp Gln Lys Ser Gln Glu Val Glu Asp
Lys 500 505 510 Thr
Lys Glu Tyr Glu Leu Leu Ser Asp Glu Leu Asn Gln Lys Ser Ala 515
520 525 Thr Leu Ala Ser Ile Asp
Ala Glu Leu Gln Lys Leu Lys Glu Met Thr 530 535
540 Asn His Gln Lys Lys Arg Ala Ala Glu Met Met
Ala Ser Leu Leu Lys 545 550 555
560 Asp Leu Ala Glu Ile Gly Ile Ala Val Gly Asn Asn Asp Val Lys Glu
565 570 575 Asp Pro
Lys Trp Glu Phe Pro Arg Lys Asn Leu Val Leu Gly Lys Thr 580
585 590 Leu Gly Glu Gly Glu Phe Gly
Lys Val Val Lys Ala Thr Ala Phe His 595 600
605 Leu Lys Gly Arg Ala Gly Tyr Thr Thr Val Ala Val
Lys Met Leu Lys 610 615 620
Glu Asn Ala Ser Pro Ser Glu Leu Arg Asp Leu Leu Ser Glu Phe Asn 625
630 635 640 Val Leu Lys
Gln Val Asn His Pro His Val Ile Lys Leu Tyr Gly Ala 645
650 655 Cys Ser Gln Asp Gly Pro Leu Leu
Leu Ile Val Glu Tyr Ala Lys Tyr 660 665
670 Gly Ser Leu Arg Gly Phe Leu Arg Glu Ser Arg Lys Val
Gly Pro Gly 675 680 685
Tyr Leu Gly Ser Gly Gly Ser Arg Asn Ser Ser Ser Leu Asp His Pro 690
695 700 Asp Glu Arg Ala
Leu Thr Met Gly Asp Leu Ile Ser Phe Ala Trp Gln 705 710
715 720 Ile Ser Gln Gly Met Gln Tyr Leu Ala
Glu Met Lys Leu Val His Arg 725 730
735 Asp Leu Ala Ala Arg Asn Ile Leu Val Ala Glu Gly Arg Lys
Met Lys 740 745 750
Ile Ser Asp Phe Gly Leu Ser Arg Asp Val Tyr Glu Glu Asp Ser Tyr
755 760 765 Val Lys Arg Ser
Gln Gly Arg Ile Pro Val Lys Trp Met Ala Ile Glu 770
775 780 Ser Leu Phe Asp His Ile Tyr Thr
Thr Gln Ser Asp Val Trp Ser Phe 785 790
795 800 Gly Val Leu Leu Trp Glu Ile Val Thr Leu Gly Gly
Asn Pro Tyr Pro 805 810
815 Gly Ile Pro Pro Glu Arg Leu Phe Asn Leu Leu Lys Thr Gly His Arg
820 825 830 Met Glu Arg
Pro Asp Asn Cys Ser Glu Glu Met Tyr Arg Leu Met Leu 835
840 845 Gln Cys Trp Lys Gln Glu Pro Asp
Lys Arg Pro Val Phe Ala Asp Ile 850 855
860 Ser Lys Asp Leu Glu Lys Met Met Val Lys Arg Arg Asp
Tyr Leu Asp 865 870 875
880 Leu Ala Ala Ser Thr Pro Ser Asp Ser Leu Ile Tyr Asp Asp Gly Leu
885 890 895 Ser Glu Glu Glu
Thr Pro Leu Val Asp Cys Asn Asn Ala Pro Leu Pro 900
905 910 Arg Ala Leu Pro Ser Thr Trp Ile Glu
Asn Lys Leu Tyr Gly Met Ser 915 920
925 Asp Pro Asn Trp Pro Gly Glu Ser Pro Val Pro Leu Thr Arg
Ala Asp 930 935 940
Gly Thr Asn Thr Gly Phe Pro Arg Tyr Pro Asn Asp Ser Val Tyr Ala 945
950 955 960 Asn Trp Met Leu Ser
Pro Ser Ala Ala Lys Leu Met Asp Thr Phe Asp 965
970 975 Ser 211040PRTHomo
sapiensmisc_featureKIF5B-RET (K16;R12 variant2) 21Met Ala Asp Leu Ala Glu
Cys Asn Ile Lys Val Met Cys Arg Phe Arg 1 5
10 15 Pro Leu Asn Glu Ser Glu Val Asn Arg Gly Asp
Lys Tyr Ile Ala Lys 20 25
30 Phe Gln Gly Glu Asp Thr Val Val Ile Ala Ser Lys Pro Tyr Ala
Phe 35 40 45 Asp
Arg Val Phe Gln Ser Ser Thr Ser Gln Glu Gln Val Tyr Asn Asp 50
55 60 Cys Ala Lys Lys Ile Val
Lys Asp Val Leu Glu Gly Tyr Asn Gly Thr 65 70
75 80 Ile Phe Ala Tyr Gly Gln Thr Ser Ser Gly Lys
Thr His Thr Met Glu 85 90
95 Gly Lys Leu His Asp Pro Glu Gly Met Gly Ile Ile Pro Arg Ile Val
100 105 110 Gln Asp
Ile Phe Asn Tyr Ile Tyr Ser Met Asp Glu Asn Leu Glu Phe 115
120 125 His Ile Lys Val Ser Tyr Phe
Glu Ile Tyr Leu Asp Lys Ile Arg Asp 130 135
140 Leu Leu Asp Val Ser Lys Thr Asn Leu Ser Val His
Glu Asp Lys Asn 145 150 155
160 Arg Val Pro Tyr Val Lys Gly Cys Thr Glu Arg Phe Val Cys Ser Pro
165 170 175 Asp Glu Val
Met Asp Thr Ile Asp Glu Gly Lys Ser Asn Arg His Val 180
185 190 Ala Val Thr Asn Met Asn Glu His
Ser Ser Arg Ser His Ser Ile Phe 195 200
205 Leu Ile Asn Val Lys Gln Glu Asn Thr Gln Thr Glu Gln
Lys Leu Ser 210 215 220
Gly Lys Leu Tyr Leu Val Asp Leu Ala Gly Ser Glu Lys Val Ser Lys 225
230 235 240 Thr Gly Ala Glu
Gly Ala Val Leu Asp Glu Ala Lys Asn Ile Asn Lys 245
250 255 Ser Leu Ser Ala Leu Gly Asn Val Ile
Ser Ala Leu Ala Glu Gly Ser 260 265
270 Thr Tyr Val Pro Tyr Arg Asp Ser Lys Met Thr Arg Ile Leu
Gln Asp 275 280 285
Ser Leu Gly Gly Asn Cys Arg Thr Thr Ile Val Ile Cys Cys Ser Pro 290
295 300 Ser Ser Tyr Asn Glu
Ser Glu Thr Lys Ser Thr Leu Leu Phe Gly Gln 305 310
315 320 Arg Ala Lys Thr Ile Lys Asn Thr Val Cys
Val Asn Val Glu Leu Thr 325 330
335 Ala Glu Gln Trp Lys Lys Lys Tyr Glu Lys Glu Lys Glu Lys Asn
Lys 340 345 350 Ile
Leu Arg Asn Thr Ile Gln Trp Leu Glu Asn Glu Leu Asn Arg Trp 355
360 365 Arg Asn Gly Glu Thr Val
Pro Ile Asp Glu Gln Phe Asp Lys Glu Lys 370 375
380 Ala Asn Leu Glu Ala Phe Thr Val Asp Lys Asp
Ile Thr Leu Thr Asn 385 390 395
400 Asp Lys Pro Ala Thr Ala Ile Gly Val Ile Gly Asn Phe Thr Asp Ala
405 410 415 Glu Arg
Arg Lys Cys Glu Glu Glu Ile Ala Lys Leu Tyr Lys Gln Leu 420
425 430 Asp Asp Lys Asp Glu Glu Ile
Asn Gln Gln Ser Gln Leu Val Glu Lys 435 440
445 Leu Lys Thr Gln Met Leu Asp Gln Glu Glu Leu Leu
Ala Ser Thr Arg 450 455 460
Arg Asp Gln Asp Asn Met Gln Ala Glu Leu Asn Arg Leu Gln Ala Glu 465
470 475 480 Asn Asp Ala
Ser Lys Glu Glu Val Lys Glu Val Leu Gln Ala Leu Glu 485
490 495 Glu Leu Ala Val Asn Tyr Asp Gln
Lys Ser Gln Glu Val Glu Asp Lys 500 505
510 Thr Lys Glu Tyr Glu Leu Leu Ser Asp Glu Leu Asn Gln
Lys Ser Ala 515 520 525
Thr Leu Ala Ser Ile Asp Ala Glu Leu Gln Lys Leu Lys Glu Met Thr 530
535 540 Asn His Gln Lys
Lys Arg Ala Ala Glu Met Met Ala Ser Leu Leu Lys 545 550
555 560 Asp Leu Ala Glu Ile Gly Ile Ala Val
Gly Asn Asn Asp Val Lys Gln 565 570
575 Pro Glu Gly Thr Gly Met Ile Asp Glu Glu Phe Thr Val Ala
Arg Leu 580 585 590
Tyr Ile Ser Lys Met Lys Ser Glu Val Lys Thr Met Val Lys Arg Cys
595 600 605 Lys Gln Leu Glu
Ser Thr Gln Thr Glu Ser Asn Lys Lys Met Glu Glu 610
615 620 Asn Glu Lys Glu Leu Ala Ala Cys
Gln Leu Arg Ile Ser Gln Glu Asp 625 630
635 640 Pro Lys Trp Glu Phe Pro Arg Lys Asn Leu Val Leu
Gly Lys Thr Leu 645 650
655 Gly Glu Gly Glu Phe Gly Lys Val Val Lys Ala Thr Ala Phe His Leu
660 665 670 Lys Gly Arg
Ala Gly Tyr Thr Thr Val Ala Val Lys Met Leu Lys Glu 675
680 685 Asn Ala Ser Pro Ser Glu Leu Arg
Asp Leu Leu Ser Glu Phe Asn Val 690 695
700 Leu Lys Gln Val Asn His Pro His Val Ile Lys Leu Tyr
Gly Ala Cys 705 710 715
720 Ser Gln Asp Gly Pro Leu Leu Leu Ile Val Glu Tyr Ala Lys Tyr Gly
725 730 735 Ser Leu Arg Gly
Phe Leu Arg Glu Ser Arg Lys Val Gly Pro Gly Tyr 740
745 750 Leu Gly Ser Gly Gly Ser Arg Asn Ser
Ser Ser Leu Asp His Pro Asp 755 760
765 Glu Arg Ala Leu Thr Met Gly Asp Leu Ile Ser Phe Ala Trp
Gln Ile 770 775 780
Ser Gln Gly Met Gln Tyr Leu Ala Glu Met Lys Leu Val His Arg Asp 785
790 795 800 Leu Ala Ala Arg Asn
Ile Leu Val Ala Glu Gly Arg Lys Met Lys Ile 805
810 815 Ser Asp Phe Gly Leu Ser Arg Asp Val Tyr
Glu Glu Asp Ser Tyr Val 820 825
830 Lys Arg Ser Gln Gly Arg Ile Pro Val Lys Trp Met Ala Ile Glu
Ser 835 840 845 Leu
Phe Asp His Ile Tyr Thr Thr Gln Ser Asp Val Trp Ser Phe Gly 850
855 860 Val Leu Leu Trp Glu Ile
Val Thr Leu Gly Gly Asn Pro Tyr Pro Gly 865 870
875 880 Ile Pro Pro Glu Arg Leu Phe Asn Leu Leu Lys
Thr Gly His Arg Met 885 890
895 Glu Arg Pro Asp Asn Cys Ser Glu Glu Met Tyr Arg Leu Met Leu Gln
900 905 910 Cys Trp
Lys Gln Glu Pro Asp Lys Arg Pro Val Phe Ala Asp Ile Ser 915
920 925 Lys Asp Leu Glu Lys Met Met
Val Lys Arg Arg Asp Tyr Leu Asp Leu 930 935
940 Ala Ala Ser Thr Pro Ser Asp Ser Leu Ile Tyr Asp
Asp Gly Leu Ser 945 950 955
960 Glu Glu Glu Thr Pro Leu Val Asp Cys Asn Asn Ala Pro Leu Pro Arg
965 970 975 Ala Leu Pro
Ser Thr Trp Ile Glu Asn Lys Leu Tyr Gly Met Ser Asp 980
985 990 Pro Asn Trp Pro Gly Glu Ser Pro
Val Pro Leu Thr Arg Ala Asp Gly 995 1000
1005 Thr Asn Thr Gly Phe Pro Arg Tyr Pro Asn Asp
Ser Val Tyr Ala 1010 1015 1020
Asn Trp Met Leu Ser Pro Ser Ala Ala Lys Leu Met Asp Thr Phe
1025 1030 1035 Asp Ser
1040 221215PRTHomo sapiensmisc_featureKIF5B-RET (K22;R12 variant2) 22Met
Ala Asp Leu Ala Glu Cys Asn Ile Lys Val Met Cys Arg Phe Arg 1
5 10 15 Pro Leu Asn Glu Ser Glu
Val Asn Arg Gly Asp Lys Tyr Ile Ala Lys 20
25 30 Phe Gln Gly Glu Asp Thr Val Val Ile Ala
Ser Lys Pro Tyr Ala Phe 35 40
45 Asp Arg Val Phe Gln Ser Ser Thr Ser Gln Glu Gln Val Tyr
Asn Asp 50 55 60
Cys Ala Lys Lys Ile Val Lys Asp Val Leu Glu Gly Tyr Asn Gly Thr 65
70 75 80 Ile Phe Ala Tyr Gly
Gln Thr Ser Ser Gly Lys Thr His Thr Met Glu 85
90 95 Gly Lys Leu His Asp Pro Glu Gly Met Gly
Ile Ile Pro Arg Ile Val 100 105
110 Gln Asp Ile Phe Asn Tyr Ile Tyr Ser Met Asp Glu Asn Leu Glu
Phe 115 120 125 His
Ile Lys Val Ser Tyr Phe Glu Ile Tyr Leu Asp Lys Ile Arg Asp 130
135 140 Leu Leu Asp Val Ser Lys
Thr Asn Leu Ser Val His Glu Asp Lys Asn 145 150
155 160 Arg Val Pro Tyr Val Lys Gly Cys Thr Glu Arg
Phe Val Cys Ser Pro 165 170
175 Asp Glu Val Met Asp Thr Ile Asp Glu Gly Lys Ser Asn Arg His Val
180 185 190 Ala Val
Thr Asn Met Asn Glu His Ser Ser Arg Ser His Ser Ile Phe 195
200 205 Leu Ile Asn Val Lys Gln Glu
Asn Thr Gln Thr Glu Gln Lys Leu Ser 210 215
220 Gly Lys Leu Tyr Leu Val Asp Leu Ala Gly Ser Glu
Lys Val Ser Lys 225 230 235
240 Thr Gly Ala Glu Gly Ala Val Leu Asp Glu Ala Lys Asn Ile Asn Lys
245 250 255 Ser Leu Ser
Ala Leu Gly Asn Val Ile Ser Ala Leu Ala Glu Gly Ser 260
265 270 Thr Tyr Val Pro Tyr Arg Asp Ser
Lys Met Thr Arg Ile Leu Gln Asp 275 280
285 Ser Leu Gly Gly Asn Cys Arg Thr Thr Ile Val Ile Cys
Cys Ser Pro 290 295 300
Ser Ser Tyr Asn Glu Ser Glu Thr Lys Ser Thr Leu Leu Phe Gly Gln 305
310 315 320 Arg Ala Lys Thr
Ile Lys Asn Thr Val Cys Val Asn Val Glu Leu Thr 325
330 335 Ala Glu Gln Trp Lys Lys Lys Tyr Glu
Lys Glu Lys Glu Lys Asn Lys 340 345
350 Ile Leu Arg Asn Thr Ile Gln Trp Leu Glu Asn Glu Leu Asn
Arg Trp 355 360 365
Arg Asn Gly Glu Thr Val Pro Ile Asp Glu Gln Phe Asp Lys Glu Lys 370
375 380 Ala Asn Leu Glu Ala
Phe Thr Val Asp Lys Asp Ile Thr Leu Thr Asn 385 390
395 400 Asp Lys Pro Ala Thr Ala Ile Gly Val Ile
Gly Asn Phe Thr Asp Ala 405 410
415 Glu Arg Arg Lys Cys Glu Glu Glu Ile Ala Lys Leu Tyr Lys Gln
Leu 420 425 430 Asp
Asp Lys Asp Glu Glu Ile Asn Gln Gln Ser Gln Leu Val Glu Lys 435
440 445 Leu Lys Thr Gln Met Leu
Asp Gln Glu Glu Leu Leu Ala Ser Thr Arg 450 455
460 Arg Asp Gln Asp Asn Met Gln Ala Glu Leu Asn
Arg Leu Gln Ala Glu 465 470 475
480 Asn Asp Ala Ser Lys Glu Glu Val Lys Glu Val Leu Gln Ala Leu Glu
485 490 495 Glu Leu
Ala Val Asn Tyr Asp Gln Lys Ser Gln Glu Val Glu Asp Lys 500
505 510 Thr Lys Glu Tyr Glu Leu Leu
Ser Asp Glu Leu Asn Gln Lys Ser Ala 515 520
525 Thr Leu Ala Ser Ile Asp Ala Glu Leu Gln Lys Leu
Lys Glu Met Thr 530 535 540
Asn His Gln Lys Lys Arg Ala Ala Glu Met Met Ala Ser Leu Leu Lys 545
550 555 560 Asp Leu Ala
Glu Ile Gly Ile Ala Val Gly Asn Asn Asp Val Lys Gln 565
570 575 Pro Glu Gly Thr Gly Met Ile Asp
Glu Glu Phe Thr Val Ala Arg Leu 580 585
590 Tyr Ile Ser Lys Met Lys Ser Glu Val Lys Thr Met Val
Lys Arg Cys 595 600 605
Lys Gln Leu Glu Ser Thr Gln Thr Glu Ser Asn Lys Lys Met Glu Glu 610
615 620 Asn Glu Lys Glu
Leu Ala Ala Cys Gln Leu Arg Ile Ser Gln His Glu 625 630
635 640 Ala Lys Ile Lys Ser Leu Thr Glu Tyr
Leu Gln Asn Val Glu Gln Lys 645 650
655 Lys Arg Gln Leu Glu Glu Ser Val Asp Ala Leu Ser Glu Glu
Leu Val 660 665 670
Gln Leu Arg Ala Gln Glu Lys Val His Glu Met Glu Lys Glu His Leu
675 680 685 Asn Lys Val Gln
Thr Ala Asn Glu Val Lys Gln Ala Val Glu Gln Gln 690
695 700 Ile Gln Ser His Arg Glu Thr His
Gln Lys Gln Ile Ser Ser Leu Arg 705 710
715 720 Asp Glu Val Glu Ala Lys Ala Lys Leu Ile Thr Asp
Leu Gln Asp Gln 725 730
735 Asn Gln Lys Met Met Leu Glu Gln Glu Arg Leu Arg Val Glu His Glu
740 745 750 Lys Leu Lys
Ala Thr Asp Gln Glu Lys Ser Arg Lys Leu His Glu Leu 755
760 765 Thr Val Met Gln Asp Arg Arg Glu
Gln Ala Arg Gln Asp Leu Lys Gly 770 775
780 Leu Glu Glu Thr Val Ala Lys Glu Leu Gln Thr Leu His
Asn Leu Arg 785 790 795
800 Lys Leu Phe Val Gln Asp Leu Ala Thr Arg Val Lys Lys Glu Asp Pro
805 810 815 Lys Trp Glu Phe
Pro Arg Lys Asn Leu Val Leu Gly Lys Thr Leu Gly 820
825 830 Glu Gly Glu Phe Gly Lys Val Val Lys
Ala Thr Ala Phe His Leu Lys 835 840
845 Gly Arg Ala Gly Tyr Thr Thr Val Ala Val Lys Met Leu Lys
Glu Asn 850 855 860
Ala Ser Pro Ser Glu Leu Arg Asp Leu Leu Ser Glu Phe Asn Val Leu 865
870 875 880 Lys Gln Val Asn His
Pro His Val Ile Lys Leu Tyr Gly Ala Cys Ser 885
890 895 Gln Asp Gly Pro Leu Leu Leu Ile Val Glu
Tyr Ala Lys Tyr Gly Ser 900 905
910 Leu Arg Gly Phe Leu Arg Glu Ser Arg Lys Val Gly Pro Gly Tyr
Leu 915 920 925 Gly
Ser Gly Gly Ser Arg Asn Ser Ser Ser Leu Asp His Pro Asp Glu 930
935 940 Arg Ala Leu Thr Met Gly
Asp Leu Ile Ser Phe Ala Trp Gln Ile Ser 945 950
955 960 Gln Gly Met Gln Tyr Leu Ala Glu Met Lys Leu
Val His Arg Asp Leu 965 970
975 Ala Ala Arg Asn Ile Leu Val Ala Glu Gly Arg Lys Met Lys Ile Ser
980 985 990 Asp Phe
Gly Leu Ser Arg Asp Val Tyr Glu Glu Asp Ser Tyr Val Lys 995
1000 1005 Arg Ser Gln Gly Arg
Ile Pro Val Lys Trp Met Ala Ile Glu Ser 1010 1015
1020 Leu Phe Asp His Ile Tyr Thr Thr Gln Ser
Asp Val Trp Ser Phe 1025 1030 1035
Gly Val Leu Leu Trp Glu Ile Val Thr Leu Gly Gly Asn Pro Tyr
1040 1045 1050 Pro Gly
Ile Pro Pro Glu Arg Leu Phe Asn Leu Leu Lys Thr Gly 1055
1060 1065 His Arg Met Glu Arg Pro Asp
Asn Cys Ser Glu Glu Met Tyr Arg 1070 1075
1080 Leu Met Leu Gln Cys Trp Lys Gln Glu Pro Asp Lys
Arg Pro Val 1085 1090 1095
Phe Ala Asp Ile Ser Lys Asp Leu Glu Lys Met Met Val Lys Arg 1100
1105 1110 Arg Asp Tyr Leu Asp
Leu Ala Ala Ser Thr Pro Ser Asp Ser Leu 1115 1120
1125 Ile Tyr Asp Asp Gly Leu Ser Glu Glu Glu
Thr Pro Leu Val Asp 1130 1135 1140
Cys Asn Asn Ala Pro Leu Pro Arg Ala Leu Pro Ser Thr Trp Ile
1145 1150 1155 Glu Asn
Lys Leu Tyr Gly Met Ser Asp Pro Asn Trp Pro Gly Glu 1160
1165 1170 Ser Pro Val Pro Leu Thr Arg
Ala Asp Gly Thr Asn Thr Gly Phe 1175 1180
1185 Pro Arg Tyr Pro Asn Asp Ser Val Tyr Ala Asn Trp
Met Leu Ser 1190 1195 1200
Pro Ser Ala Ala Lys Leu Met Asp Thr Phe Asp Ser 1205
1210 1215 231250PRTHomo sapiensmisc_featureKIF5B-RET
(K23;R12 variant2) 23Met Ala Asp Leu Ala Glu Cys Asn Ile Lys Val Met Cys
Arg Phe Arg 1 5 10 15
Pro Leu Asn Glu Ser Glu Val Asn Arg Gly Asp Lys Tyr Ile Ala Lys
20 25 30 Phe Gln Gly Glu
Asp Thr Val Val Ile Ala Ser Lys Pro Tyr Ala Phe 35
40 45 Asp Arg Val Phe Gln Ser Ser Thr Ser
Gln Glu Gln Val Tyr Asn Asp 50 55
60 Cys Ala Lys Lys Ile Val Lys Asp Val Leu Glu Gly Tyr
Asn Gly Thr 65 70 75
80 Ile Phe Ala Tyr Gly Gln Thr Ser Ser Gly Lys Thr His Thr Met Glu
85 90 95 Gly Lys Leu His
Asp Pro Glu Gly Met Gly Ile Ile Pro Arg Ile Val 100
105 110 Gln Asp Ile Phe Asn Tyr Ile Tyr Ser
Met Asp Glu Asn Leu Glu Phe 115 120
125 His Ile Lys Val Ser Tyr Phe Glu Ile Tyr Leu Asp Lys Ile
Arg Asp 130 135 140
Leu Leu Asp Val Ser Lys Thr Asn Leu Ser Val His Glu Asp Lys Asn 145
150 155 160 Arg Val Pro Tyr Val
Lys Gly Cys Thr Glu Arg Phe Val Cys Ser Pro 165
170 175 Asp Glu Val Met Asp Thr Ile Asp Glu Gly
Lys Ser Asn Arg His Val 180 185
190 Ala Val Thr Asn Met Asn Glu His Ser Ser Arg Ser His Ser Ile
Phe 195 200 205 Leu
Ile Asn Val Lys Gln Glu Asn Thr Gln Thr Glu Gln Lys Leu Ser 210
215 220 Gly Lys Leu Tyr Leu Val
Asp Leu Ala Gly Ser Glu Lys Val Ser Lys 225 230
235 240 Thr Gly Ala Glu Gly Ala Val Leu Asp Glu Ala
Lys Asn Ile Asn Lys 245 250
255 Ser Leu Ser Ala Leu Gly Asn Val Ile Ser Ala Leu Ala Glu Gly Ser
260 265 270 Thr Tyr
Val Pro Tyr Arg Asp Ser Lys Met Thr Arg Ile Leu Gln Asp 275
280 285 Ser Leu Gly Gly Asn Cys Arg
Thr Thr Ile Val Ile Cys Cys Ser Pro 290 295
300 Ser Ser Tyr Asn Glu Ser Glu Thr Lys Ser Thr Leu
Leu Phe Gly Gln 305 310 315
320 Arg Ala Lys Thr Ile Lys Asn Thr Val Cys Val Asn Val Glu Leu Thr
325 330 335 Ala Glu Gln
Trp Lys Lys Lys Tyr Glu Lys Glu Lys Glu Lys Asn Lys 340
345 350 Ile Leu Arg Asn Thr Ile Gln Trp
Leu Glu Asn Glu Leu Asn Arg Trp 355 360
365 Arg Asn Gly Glu Thr Val Pro Ile Asp Glu Gln Phe Asp
Lys Glu Lys 370 375 380
Ala Asn Leu Glu Ala Phe Thr Val Asp Lys Asp Ile Thr Leu Thr Asn 385
390 395 400 Asp Lys Pro Ala
Thr Ala Ile Gly Val Ile Gly Asn Phe Thr Asp Ala 405
410 415 Glu Arg Arg Lys Cys Glu Glu Glu Ile
Ala Lys Leu Tyr Lys Gln Leu 420 425
430 Asp Asp Lys Asp Glu Glu Ile Asn Gln Gln Ser Gln Leu Val
Glu Lys 435 440 445
Leu Lys Thr Gln Met Leu Asp Gln Glu Glu Leu Leu Ala Ser Thr Arg 450
455 460 Arg Asp Gln Asp Asn
Met Gln Ala Glu Leu Asn Arg Leu Gln Ala Glu 465 470
475 480 Asn Asp Ala Ser Lys Glu Glu Val Lys Glu
Val Leu Gln Ala Leu Glu 485 490
495 Glu Leu Ala Val Asn Tyr Asp Gln Lys Ser Gln Glu Val Glu Asp
Lys 500 505 510 Thr
Lys Glu Tyr Glu Leu Leu Ser Asp Glu Leu Asn Gln Lys Ser Ala 515
520 525 Thr Leu Ala Ser Ile Asp
Ala Glu Leu Gln Lys Leu Lys Glu Met Thr 530 535
540 Asn His Gln Lys Lys Arg Ala Ala Glu Met Met
Ala Ser Leu Leu Lys 545 550 555
560 Asp Leu Ala Glu Ile Gly Ile Ala Val Gly Asn Asn Asp Val Lys Gln
565 570 575 Pro Glu
Gly Thr Gly Met Ile Asp Glu Glu Phe Thr Val Ala Arg Leu 580
585 590 Tyr Ile Ser Lys Met Lys Ser
Glu Val Lys Thr Met Val Lys Arg Cys 595 600
605 Lys Gln Leu Glu Ser Thr Gln Thr Glu Ser Asn Lys
Lys Met Glu Glu 610 615 620
Asn Glu Lys Glu Leu Ala Ala Cys Gln Leu Arg Ile Ser Gln His Glu 625
630 635 640 Ala Lys Ile
Lys Ser Leu Thr Glu Tyr Leu Gln Asn Val Glu Gln Lys 645
650 655 Lys Arg Gln Leu Glu Glu Ser Val
Asp Ala Leu Ser Glu Glu Leu Val 660 665
670 Gln Leu Arg Ala Gln Glu Lys Val His Glu Met Glu Lys
Glu His Leu 675 680 685
Asn Lys Val Gln Thr Ala Asn Glu Val Lys Gln Ala Val Glu Gln Gln 690
695 700 Ile Gln Ser His
Arg Glu Thr His Gln Lys Gln Ile Ser Ser Leu Arg 705 710
715 720 Asp Glu Val Glu Ala Lys Ala Lys Leu
Ile Thr Asp Leu Gln Asp Gln 725 730
735 Asn Gln Lys Met Met Leu Glu Gln Glu Arg Leu Arg Val Glu
His Glu 740 745 750
Lys Leu Lys Ala Thr Asp Gln Glu Lys Ser Arg Lys Leu His Glu Leu
755 760 765 Thr Val Met Gln
Asp Arg Arg Glu Gln Ala Arg Gln Asp Leu Lys Gly 770
775 780 Leu Glu Glu Thr Val Ala Lys Glu
Leu Gln Thr Leu His Asn Leu Arg 785 790
795 800 Lys Leu Phe Val Gln Asp Leu Ala Thr Arg Val Lys
Lys Ser Ala Glu 805 810
815 Ile Asp Ser Asp Asp Thr Gly Gly Ser Ala Ala Gln Lys Gln Lys Ile
820 825 830 Ser Phe Leu
Glu Asn Asn Leu Glu Gln Leu Thr Lys Val His Lys Gln 835
840 845 Glu Asp Pro Lys Trp Glu Phe Pro
Arg Lys Asn Leu Val Leu Gly Lys 850 855
860 Thr Leu Gly Glu Gly Glu Phe Gly Lys Val Val Lys Ala
Thr Ala Phe 865 870 875
880 His Leu Lys Gly Arg Ala Gly Tyr Thr Thr Val Ala Val Lys Met Leu
885 890 895 Lys Glu Asn Ala
Ser Pro Ser Glu Leu Arg Asp Leu Leu Ser Glu Phe 900
905 910 Asn Val Leu Lys Gln Val Asn His Pro
His Val Ile Lys Leu Tyr Gly 915 920
925 Ala Cys Ser Gln Asp Gly Pro Leu Leu Leu Ile Val Glu Tyr
Ala Lys 930 935 940
Tyr Gly Ser Leu Arg Gly Phe Leu Arg Glu Ser Arg Lys Val Gly Pro 945
950 955 960 Gly Tyr Leu Gly Ser
Gly Gly Ser Arg Asn Ser Ser Ser Leu Asp His 965
970 975 Pro Asp Glu Arg Ala Leu Thr Met Gly Asp
Leu Ile Ser Phe Ala Trp 980 985
990 Gln Ile Ser Gln Gly Met Gln Tyr Leu Ala Glu Met Lys Leu
Val His 995 1000 1005
Arg Asp Leu Ala Ala Arg Asn Ile Leu Val Ala Glu Gly Arg Lys 1010
1015 1020 Met Lys Ile Ser Asp
Phe Gly Leu Ser Arg Asp Val Tyr Glu Glu 1025 1030
1035 Asp Ser Tyr Val Lys Arg Ser Gln Gly Arg
Ile Pro Val Lys Trp 1040 1045 1050
Met Ala Ile Glu Ser Leu Phe Asp His Ile Tyr Thr Thr Gln Ser
1055 1060 1065 Asp Val
Trp Ser Phe Gly Val Leu Leu Trp Glu Ile Val Thr Leu 1070
1075 1080 Gly Gly Asn Pro Tyr Pro Gly
Ile Pro Pro Glu Arg Leu Phe Asn 1085 1090
1095 Leu Leu Lys Thr Gly His Arg Met Glu Arg Pro Asp
Asn Cys Ser 1100 1105 1110
Glu Glu Met Tyr Arg Leu Met Leu Gln Cys Trp Lys Gln Glu Pro 1115
1120 1125 Asp Lys Arg Pro Val
Phe Ala Asp Ile Ser Lys Asp Leu Glu Lys 1130 1135
1140 Met Met Val Lys Arg Arg Asp Tyr Leu Asp
Leu Ala Ala Ser Thr 1145 1150 1155
Pro Ser Asp Ser Leu Ile Tyr Asp Asp Gly Leu Ser Glu Glu Glu
1160 1165 1170 Thr Pro
Leu Val Asp Cys Asn Asn Ala Pro Leu Pro Arg Ala Leu 1175
1180 1185 Pro Ser Thr Trp Ile Glu Asn
Lys Leu Tyr Gly Met Ser Asp Pro 1190 1195
1200 Asn Trp Pro Gly Glu Ser Pro Val Pro Leu Thr Arg
Ala Asp Gly 1205 1210 1215
Thr Asn Thr Gly Phe Pro Arg Tyr Pro Asn Asp Ser Val Tyr Ala 1220
1225 1230 Asn Trp Met Leu Ser
Pro Ser Ala Ala Lys Leu Met Asp Thr Phe 1235 1240
1245 Asp Ser 1250 24985PRTHomo
sapiensmisc_featureKIF5B-RET (K15;R11 variant4) 24Met Ala Asp Leu Ala Glu
Cys Asn Ile Lys Val Met Cys Arg Phe Arg 1 5
10 15 Pro Leu Asn Glu Ser Glu Val Asn Arg Gly Asp
Lys Tyr Ile Ala Lys 20 25
30 Phe Gln Gly Glu Asp Thr Val Val Ile Ala Ser Lys Pro Tyr Ala
Phe 35 40 45 Asp
Arg Val Phe Gln Ser Ser Thr Ser Gln Glu Gln Val Tyr Asn Asp 50
55 60 Cys Ala Lys Lys Ile Val
Lys Asp Val Leu Glu Gly Tyr Asn Gly Thr 65 70
75 80 Ile Phe Ala Tyr Gly Gln Thr Ser Ser Gly Lys
Thr His Thr Met Glu 85 90
95 Gly Lys Leu His Asp Pro Glu Gly Met Gly Ile Ile Pro Arg Ile Val
100 105 110 Gln Asp
Ile Phe Asn Tyr Ile Tyr Ser Met Asp Glu Asn Leu Glu Phe 115
120 125 His Ile Lys Val Ser Tyr Phe
Glu Ile Tyr Leu Asp Lys Ile Arg Asp 130 135
140 Leu Leu Asp Val Ser Lys Thr Asn Leu Ser Val His
Glu Asp Lys Asn 145 150 155
160 Arg Val Pro Tyr Val Lys Gly Cys Thr Glu Arg Phe Val Cys Ser Pro
165 170 175 Asp Glu Val
Met Asp Thr Ile Asp Glu Gly Lys Ser Asn Arg His Val 180
185 190 Ala Val Thr Asn Met Asn Glu His
Ser Ser Arg Ser His Ser Ile Phe 195 200
205 Leu Ile Asn Val Lys Gln Glu Asn Thr Gln Thr Glu Gln
Lys Leu Ser 210 215 220
Gly Lys Leu Tyr Leu Val Asp Leu Ala Gly Ser Glu Lys Val Ser Lys 225
230 235 240 Thr Gly Ala Glu
Gly Ala Val Leu Asp Glu Ala Lys Asn Ile Asn Lys 245
250 255 Ser Leu Ser Ala Leu Gly Asn Val Ile
Ser Ala Leu Ala Glu Gly Ser 260 265
270 Thr Tyr Val Pro Tyr Arg Asp Ser Lys Met Thr Arg Ile Leu
Gln Asp 275 280 285
Ser Leu Gly Gly Asn Cys Arg Thr Thr Ile Val Ile Cys Cys Ser Pro 290
295 300 Ser Ser Tyr Asn Glu
Ser Glu Thr Lys Ser Thr Leu Leu Phe Gly Gln 305 310
315 320 Arg Ala Lys Thr Ile Lys Asn Thr Val Cys
Val Asn Val Glu Leu Thr 325 330
335 Ala Glu Gln Trp Lys Lys Lys Tyr Glu Lys Glu Lys Glu Lys Asn
Lys 340 345 350 Ile
Leu Arg Asn Thr Ile Gln Trp Leu Glu Asn Glu Leu Asn Arg Trp 355
360 365 Arg Asn Gly Glu Thr Val
Pro Ile Asp Glu Gln Phe Asp Lys Glu Lys 370 375
380 Ala Asn Leu Glu Ala Phe Thr Val Asp Lys Asp
Ile Thr Leu Thr Asn 385 390 395
400 Asp Lys Pro Ala Thr Ala Ile Gly Val Ile Gly Asn Phe Thr Asp Ala
405 410 415 Glu Arg
Arg Lys Cys Glu Glu Glu Ile Ala Lys Leu Tyr Lys Gln Leu 420
425 430 Asp Asp Lys Asp Glu Glu Ile
Asn Gln Gln Ser Gln Leu Val Glu Lys 435 440
445 Leu Lys Thr Gln Met Leu Asp Gln Glu Glu Leu Leu
Ala Ser Thr Arg 450 455 460
Arg Asp Gln Asp Asn Met Gln Ala Glu Leu Asn Arg Leu Gln Ala Glu 465
470 475 480 Asn Asp Ala
Ser Lys Glu Glu Val Lys Glu Val Leu Gln Ala Leu Glu 485
490 495 Glu Leu Ala Val Asn Tyr Asp Gln
Lys Ser Gln Glu Val Glu Asp Lys 500 505
510 Thr Lys Glu Tyr Glu Leu Leu Ser Asp Glu Leu Asn Gln
Lys Ser Ala 515 520 525
Thr Leu Ala Ser Ile Asp Ala Glu Leu Gln Lys Leu Lys Glu Met Thr 530
535 540 Asn His Gln Lys
Lys Arg Ala Ala Glu Met Met Ala Ser Leu Leu Lys 545 550
555 560 Asp Leu Ala Glu Ile Gly Ile Ala Val
Gly Asn Asn Asp Val Lys Phe 565 570
575 Ala His Lys Pro Pro Ile Ser Ser Ala Glu Met Thr Phe Arg
Arg Pro 580 585 590
Ala Gln Ala Phe Pro Val Ser Tyr Ser Ser Ser Gly Ala Arg Arg Pro
595 600 605 Ser Leu Asp Ser
Met Glu Asn Gln Val Ser Val Asp Ala Phe Lys Ile 610
615 620 Leu Glu Asp Pro Lys Trp Glu Phe
Pro Arg Lys Asn Leu Val Leu Gly 625 630
635 640 Lys Thr Leu Gly Glu Gly Glu Phe Gly Lys Val Val
Lys Ala Thr Ala 645 650
655 Phe His Leu Lys Gly Arg Ala Gly Tyr Thr Thr Val Ala Val Lys Met
660 665 670 Leu Lys Glu
Asn Ala Ser Pro Ser Glu Leu Arg Asp Leu Leu Ser Glu 675
680 685 Phe Asn Val Leu Lys Gln Val Asn
His Pro His Val Ile Lys Leu Tyr 690 695
700 Gly Ala Cys Ser Gln Asp Gly Pro Leu Leu Leu Ile Val
Glu Tyr Ala 705 710 715
720 Lys Tyr Gly Ser Leu Arg Gly Phe Leu Arg Glu Ser Arg Lys Val Gly
725 730 735 Pro Gly Tyr Leu
Gly Ser Gly Gly Ser Arg Asn Ser Ser Ser Leu Asp 740
745 750 His Pro Asp Glu Arg Ala Leu Thr Met
Gly Asp Leu Ile Ser Phe Ala 755 760
765 Trp Gln Ile Ser Gln Gly Met Gln Tyr Leu Ala Glu Met Lys
Leu Val 770 775 780
His Arg Asp Leu Ala Ala Arg Asn Ile Leu Val Ala Glu Gly Arg Lys 785
790 795 800 Met Lys Ile Ser Asp
Phe Gly Leu Ser Arg Asp Val Tyr Glu Glu Asp 805
810 815 Ser Tyr Val Lys Arg Ser Gln Gly Arg Ile
Pro Val Lys Trp Met Ala 820 825
830 Ile Glu Ser Leu Phe Asp His Ile Tyr Thr Thr Gln Ser Asp Val
Trp 835 840 845 Ser
Phe Gly Val Leu Leu Trp Glu Ile Val Thr Leu Gly Gly Asn Pro 850
855 860 Tyr Pro Gly Ile Pro Pro
Glu Arg Leu Phe Asn Leu Leu Lys Thr Gly 865 870
875 880 His Arg Met Glu Arg Pro Asp Asn Cys Ser Glu
Glu Met Tyr Arg Leu 885 890
895 Met Leu Gln Cys Trp Lys Gln Glu Pro Asp Lys Arg Pro Val Phe Ala
900 905 910 Asp Ile
Ser Lys Asp Leu Glu Lys Met Met Val Lys Arg Arg Asp Tyr 915
920 925 Leu Asp Leu Ala Ala Ser Thr
Pro Ser Asp Ser Leu Ile Tyr Asp Asp 930 935
940 Gly Leu Ser Glu Glu Glu Thr Pro Leu Val Asp Cys
Asn Asn Ala Pro 945 950 955
960 Leu Pro Arg Ala Leu Pro Ser Thr Trp Ile Glu Asn Lys Leu Tyr Gly
965 970 975 Arg Ile Ser
His Ala Phe Thr Arg Phe 980 985 251512DNAHomo
sapiensmisc_featureCCDC6-RET variant a (AB698668.1) 25atggcggaca
gcgccagcga gagcgacacg gacggggcgg ggggcaacag cagcagctcg 60gccgccatgc
agtcgtcctg ctcgtcgacc tcgggcggcg gcggtggcgg cgggggaggc 120ggcggcggtg
ggaagtcggg gggcattgtc atctcgccgt tccgcctgga ggagctcacc 180aaccgcctgg
cctcgctgca gcaagagaac aaggtgctga agatagagct ggagacctac 240aaactgaagt
gcaaggcact gcaggaggag aaccgcgacc tgcgcaaagc cagcgttacc 300atcgaggatc
caaagtggga attccctcgg aagaacttgg ttcttggaaa aactctagga 360gaaggcgaat
ttggaaaagt ggtcaaggca acggccttcc atctgaaagg cagagcaggg 420tacaccacgg
tggccgtgaa gatgctgaaa gagaacgcct ccccgagtga gctgcgagac 480ctgctgtcag
agttcaacgt cctgaagcag gtcaaccacc cacatgtcat caaattgtat 540ggggcctgca
gccaggatgg cccgctcctc ctcatcgtgg agtacgccaa atacggctcc 600ctgcggggct
tcctccgcga gagccgcaaa gtggggcctg gctacctggg cagtggaggc 660agccgcaact
ccagctccct ggaccacccg gatgagcggg ccctcaccat gggcgacctc 720atctcatttg
cctggcagat ctcacagggg atgcagtatc tggccgagat gaagctcgtt 780catcgggact
tggcagccag aaacatcctg gtagctgagg ggcggaagat gaagatttcg 840gatttcggct
tgtcccgaga tgtttatgaa gaggattcct acgtgaagag gagccagggt 900cggattccag
ttaaatggat ggcaattgaa tccctttttg atcatatcta caccacgcaa 960agtgatgtat
ggtcttttgg tgtcctgctg tgggagatcg tgaccctagg gggaaacccc 1020tatcctggga
ttcctcctga gcggctcttc aaccttctga agaccggcca ccggatggag 1080aggccagaca
actgcagcga ggagatgtac cgcctgatgc tgcaatgctg gaagcaggag 1140ccggacaaaa
ggccggtgtt tgcggacatc agcaaagacc tggagaagat gatggttaag 1200aggagagact
acttggacct tgcggcgtcc actccatctg actccctgat ttatgacgac 1260ggcctctcag
aggaggagac accgctggtg gactgtaata atgcccccct ccctcgagcc 1320ctcccttcca
catggattga aaacaaactc tatggcatgt cagacccgaa ctggcctgga 1380gagagtcctg
taccactcac gagagctgat ggcactaaca ctgggtttcc aagatatcca 1440aatgatagtg
tatatgctaa ctggatgctt tcaccctcag cggcaaaatt aatggacacg 1500tttgatagtt
aa
1512261386DNAHomo sapiensmisc_featureCCDC6-RET variant c (AB698669.1)
26atggcggaca gcgccagcga gagcgacacg gacggggcgg ggggcaacag cagcagctcg
60gccgccatgc agtcgtcctg ctcgtcgacc tcgggcggcg gcggtggcgg cgggggaggc
120ggcggcggtg ggaagtcggg gggcattgtc atctcgccgt tccgcctgga ggagctcacc
180aaccgcctgg cctcgctgca gcaagagaac aaggtgctga agatagagct ggagacctac
240aaactgaagt gcaaggcact gcaggaggag aaccgcgacc tgcgcaaagc cagcgttacc
300atcgaggatc caaagtggga attccctcgg aagaacttgg ttcttggaaa aactctagga
360gaaggcgaat ttggaaaagt ggtcaaggca acggccttcc atctgaaagg cagagcaggg
420tacaccacgg tggccgtgaa gatgctgaaa gagaacgcct ccccgagtga gctgcgagac
480ctgctgtcag agttcaacgt cctgaagcag gtcaaccacc cacatgtcat caaattgtat
540ggggcctgca gccaggatgg cccgctcctc ctcatcgtgg agtacgccaa atacggctcc
600ctgcggggct tcctccgcga gagccgcaaa gtggggcctg gctacctggg cagtggaggc
660agccgcaact ccagctccct ggaccacccg gatgagcggg ccctcaccat gggcgacctc
720atctcatttg cctggcagat ctcacagggg atgcagtatc tggccgagat gaagctcgtt
780catcgggact tggcagccag aaacatcctg gtagctgagg ggcggaagat gaagatttcg
840gatttcggct tgtcccgaga tgtttatgaa gaggattcct acgtgaagag gagccagggt
900cggattccag ttaaatggat ggcaattgaa tccctttttg atcatatcta caccacgcaa
960agtgatgtat ggtcttttgg tgtcctgctg tgggagatcg tgaccctagg gggaaacccc
1020tatcctggga ttcctcctga gcggctcttc aaccttctga agaccggcca ccggatggag
1080aggccagaca actgcagcga ggagatgtac cgcctgatgc tgcaatgctg gaagcaggag
1140ccggacaaaa ggccggtgtt tgcggacatc agcaaagacc tggagaagat gatggttaag
1200aggagagact acttggacct tgcggcgtcc actccatctg actccctgat ttatgacgac
1260ggcctctcag aggaggagac accgctggtg gactgtaata atgcccccct ccctcgagcc
1320ctcccttcca catggattga aaacaaactc tatggtagaa tttcccatgc atttactaga
1380ttctag
138627503PRTHomo sapiensmisc_featureCCDC6-RET variant a (BAM36435.1)
27Met Ala Asp Ser Ala Ser Glu Ser Asp Thr Asp Gly Ala Gly Gly Asn 1
5 10 15 Ser Ser Ser Ser
Ala Ala Met Gln Ser Ser Cys Ser Ser Thr Ser Gly 20
25 30 Gly Gly Gly Gly Gly Gly Gly Gly Gly
Gly Gly Gly Lys Ser Gly Gly 35 40
45 Ile Val Ile Ser Pro Phe Arg Leu Glu Glu Leu Thr Asn Arg
Leu Ala 50 55 60
Ser Leu Gln Gln Glu Asn Lys Val Leu Lys Ile Glu Leu Glu Thr Tyr 65
70 75 80 Lys Leu Lys Cys Lys
Ala Leu Gln Glu Glu Asn Arg Asp Leu Arg Lys 85
90 95 Ala Ser Val Thr Ile Glu Asp Pro Lys
Trp Glu Phe Pro Arg Lys Asn 100 105
110 Leu Val Leu Gly Lys Thr Leu Gly Glu Gly Glu Phe Gly Lys
Val Val 115 120 125
Lys Ala Thr Ala Phe His Leu Lys Gly Arg Ala Gly Tyr Thr Thr Val 130
135 140 Ala Val Lys Met Leu
Lys Glu Asn Ala Ser Pro Ser Glu Leu Arg Asp 145 150
155 160 Leu Leu Ser Glu Phe Asn Val Leu Lys Gln
Val Asn His Pro His Val 165 170
175 Ile Lys Leu Tyr Gly Ala Cys Ser Gln Asp Gly Pro Leu Leu Leu
Ile 180 185 190 Val
Glu Tyr Ala Lys Tyr Gly Ser Leu Arg Gly Phe Leu Arg Glu Ser 195
200 205 Arg Lys Val Gly Pro Gly
Tyr Leu Gly Ser Gly Gly Ser Arg Asn Ser 210 215
220 Ser Ser Leu Asp His Pro Asp Glu Arg Ala Leu
Thr Met Gly Asp Leu 225 230 235
240 Ile Ser Phe Ala Trp Gln Ile Ser Gln Gly Met Gln Tyr Leu Ala Glu
245 250 255 Met Lys
Leu Val His Arg Asp Leu Ala Ala Arg Asn Ile Leu Val Ala 260
265 270 Glu Gly Arg Lys Met Lys Ile
Ser Asp Phe Gly Leu Ser Arg Asp Val 275 280
285 Tyr Glu Glu Asp Ser Tyr Val Lys Arg Ser Gln Gly
Arg Ile Pro Val 290 295 300
Lys Trp Met Ala Ile Glu Ser Leu Phe Asp His Ile Tyr Thr Thr Gln 305
310 315 320 Ser Asp Val
Trp Ser Phe Gly Val Leu Leu Trp Glu Ile Val Thr Leu 325
330 335 Gly Gly Asn Pro Tyr Pro Gly Ile
Pro Pro Glu Arg Leu Phe Asn Leu 340 345
350 Leu Lys Thr Gly His Arg Met Glu Arg Pro Asp Asn Cys
Ser Glu Glu 355 360 365
Met Tyr Arg Leu Met Leu Gln Cys Trp Lys Gln Glu Pro Asp Lys Arg 370
375 380 Pro Val Phe Ala
Asp Ile Ser Lys Asp Leu Glu Lys Met Met Val Lys 385 390
395 400 Arg Arg Asp Tyr Leu Asp Leu Ala Ala
Ser Thr Pro Ser Asp Ser Leu 405 410
415 Ile Tyr Asp Asp Gly Leu Ser Glu Glu Glu Thr Pro Leu Val
Asp Cys 420 425 430
Asn Asn Ala Pro Leu Pro Arg Ala Leu Pro Ser Thr Trp Ile Glu Asn
435 440 445 Lys Leu Tyr Gly
Met Ser Asp Pro Asn Trp Pro Gly Glu Ser Pro Val 450
455 460 Pro Leu Thr Arg Ala Asp Gly Thr
Asn Thr Gly Phe Pro Arg Tyr Pro 465 470
475 480 Asn Asp Ser Val Tyr Ala Asn Trp Met Leu Ser Pro
Ser Ala Ala Lys 485 490
495 Leu Met Asp Thr Phe Asp Ser 500
28461PRTHomo sapiensmisc_featureCCDC6-RET variant c (BAM36436.1) 28Met
Ala Asp Ser Ala Ser Glu Ser Asp Thr Asp Gly Ala Gly Gly Asn 1
5 10 15 Ser Ser Ser Ser Ala Ala
Met Gln Ser Ser Cys Ser Ser Thr Ser Gly 20
25 30 Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly
Gly Gly Lys Ser Gly Gly 35 40
45 Ile Val Ile Ser Pro Phe Arg Leu Glu Glu Leu Thr Asn Arg
Leu Ala 50 55 60
Ser Leu Gln Gln Glu Asn Lys Val Leu Lys Ile Glu Leu Glu Thr Tyr 65
70 75 80 Lys Leu Lys Cys Lys
Ala Leu Gln Glu Glu Asn Arg Asp Leu Arg Lys 85
90 95 Ala Ser Val Thr Ile Glu Asp Pro Lys Trp
Glu Phe Pro Arg Lys Asn 100 105
110 Leu Val Leu Gly Lys Thr Leu Gly Glu Gly Glu Phe Gly Lys Val
Val 115 120 125 Lys
Ala Thr Ala Phe His Leu Lys Gly Arg Ala Gly Tyr Thr Thr Val 130
135 140 Ala Val Lys Met Leu Lys
Glu Asn Ala Ser Pro Ser Glu Leu Arg Asp 145 150
155 160 Leu Leu Ser Glu Phe Asn Val Leu Lys Gln Val
Asn His Pro His Val 165 170
175 Ile Lys Leu Tyr Gly Ala Cys Ser Gln Asp Gly Pro Leu Leu Leu Ile
180 185 190 Val Glu
Tyr Ala Lys Tyr Gly Ser Leu Arg Gly Phe Leu Arg Glu Ser 195
200 205 Arg Lys Val Gly Pro Gly Tyr
Leu Gly Ser Gly Gly Ser Arg Asn Ser 210 215
220 Ser Ser Leu Asp His Pro Asp Glu Arg Ala Leu Thr
Met Gly Asp Leu 225 230 235
240 Ile Ser Phe Ala Trp Gln Ile Ser Gln Gly Met Gln Tyr Leu Ala Glu
245 250 255 Met Lys Leu
Val His Arg Asp Leu Ala Ala Arg Asn Ile Leu Val Ala 260
265 270 Glu Gly Arg Lys Met Lys Ile Ser
Asp Phe Gly Leu Ser Arg Asp Val 275 280
285 Tyr Glu Glu Asp Ser Tyr Val Lys Arg Ser Gln Gly Arg
Ile Pro Val 290 295 300
Lys Trp Met Ala Ile Glu Ser Leu Phe Asp His Ile Tyr Thr Thr Gln 305
310 315 320 Ser Asp Val Trp
Ser Phe Gly Val Leu Leu Trp Glu Ile Val Thr Leu 325
330 335 Gly Gly Asn Pro Tyr Pro Gly Ile Pro
Pro Glu Arg Leu Phe Asn Leu 340 345
350 Leu Lys Thr Gly His Arg Met Glu Arg Pro Asp Asn Cys Ser
Glu Glu 355 360 365
Met Tyr Arg Leu Met Leu Gln Cys Trp Lys Gln Glu Pro Asp Lys Arg 370
375 380 Pro Val Phe Ala Asp
Ile Ser Lys Asp Leu Glu Lys Met Met Val Lys 385 390
395 400 Arg Arg Asp Tyr Leu Asp Leu Ala Ala Ser
Thr Pro Ser Asp Ser Leu 405 410
415 Ile Tyr Asp Asp Gly Leu Ser Glu Glu Glu Thr Pro Leu Val Asp
Cys 420 425 430 Asn
Asn Ala Pro Leu Pro Arg Ala Leu Pro Ser Thr Trp Ile Glu Asn 435
440 445 Lys Leu Tyr Gly Arg Ile
Ser His Ala Phe Thr Arg Phe 450 455
460 295905DNAHomo sapiensmisc_featureKIF5B (NM_004521.2) 29ctcctcccgc
accgccctgt cgcccaacgg cggcctcagg agtgatcggg cagcagtcgg 60ccggccagcg
gacggcagag cgggcggacg ggtaggcccg gcctgctctt cgcgaggagg 120aagaaggtgg
ccactctccc ggtccccaga acctccccag cccccgcagt ccgcccagac 180cgtaaagggg
gacgctgagg agccgcggac gctctccccg gtgccgccgc cgctgccgcc 240gccatggctg
ccatgatgga tcggaagtga gcattagggt taacggctgc cggcgccggc 300tcttcaagtc
ccggctcccc ggccgcctcc acccggggaa gcgcagcgcg gcgcagctga 360ctgctgcctc
tcacggccct cgcgaccaca agccctcagg tccggcgcgt tccctgcaag 420actgagcggc
ggggagtggc tcccggccgc cggccccggc tgcgagaaag atggcggacc 480tggccgagtg
caacatcaaa gtgatgtgtc gcttcagacc tctcaacgag tctgaagtga 540accgcggcga
caagtacatc gccaagtttc agggagaaga cacggtcgtg atcgcgtcca 600agccttatgc
atttgatcgg gtgttccagt caagcacatc tcaagagcaa gtgtataatg 660actgtgcaaa
gaagattgtt aaagatgtac ttgaaggata taatggaaca atatttgcat 720atggacaaac
atcctctggg aagacacaca caatggaggg taaacttcat gatccagaag 780gcatgggaat
tattccaaga atagtgcaag atatttttaa ttatatttac tccatggatg 840aaaatttgga
atttcatatt aaggtttcat attttgaaat atatttggat aagataaggg 900acctgttaga
tgtttcaaag accaaccttt cagttcatga agacaaaaac cgagttccct 960atgtaaaggg
gtgcacagag cgttttgtat gtagtccaga tgaagttatg gataccatag 1020atgaaggaaa
atccaacaga catgtagcag ttacaaatat gaatgaacat agctctagga 1080gtcacagtat
atttcttatt aatgtcaaac aagagaacac acaaacggaa caaaagctga 1140gtggaaaact
ttatctggtt gatttagctg gtagtgaaaa ggttagtaaa actggagctg 1200aaggtgctgt
gctggatgaa gctaaaaaca tcaacaagtc actttctgct cttggaaatg 1260ttatttctgc
tttggctgag ggtagtacat atgttccata tcgagatagt aaaatgacaa 1320gaatccttca
agattcatta ggtggcaact gtagaaccac tattgtaatt tgctgctctc 1380catcatcata
caatgagtct gaaacaaaat ctacactctt atttggccaa agggccaaaa 1440caattaagaa
cacagtttgt gtcaatgtgg agttaactgc agaacagtgg aaaaagaagt 1500atgaaaaaga
aaaagaaaaa aataagatcc tgcggaacac tattcagtgg cttgaaaatg 1560agctcaacag
atggcgtaat ggggagacgg tgcctattga tgaacagttt gacaaagaga 1620aagccaactt
ggaagctttc acagtggata aagatattac tcttaccaat gataaaccag 1680caaccgcaat
tggagttata ggaaatttta ctgatgctga aagaagaaag tgtgaagaag 1740aaattgctaa
attatacaaa cagcttgatg acaaggatga agaaattaac cagcaaagtc 1800aactggtaga
gaaactgaag acgcaaatgt tggatcagga ggagcttttg gcatctacca 1860gaagggatca
agacaatatg caagctgagc tgaatcgcct tcaagcagaa aatgatgcct 1920ctaaagaaga
agtgaaagaa gttttacagg ccctagaaga acttgctgtc aattatgatc 1980agaagtctca
ggaagttgaa gacaaaacta aggaatatga attgcttagt gatgaattga 2040atcagaaatc
ggcaacttta gcgagtatag atgctgagct tcagaaactt aaggaaatga 2100ccaaccacca
gaaaaaacga gcagctgaga tgatggcatc tttactaaaa gaccttgcag 2160aaataggaat
tgctgtggga aataatgatg taaagcagcc tgagggaact ggcatgatag 2220atgaagagtt
cactgttgca agactctaca ttagcaaaat gaagtcagaa gtaaaaacca 2280tggtgaaacg
ttgcaagcag ttagaaagca cacaaactga gagcaacaaa aaaatggaag 2340aaaatgaaaa
ggagttagca gcatgtcagc ttcgtatctc tcaacatgaa gccaaaatca 2400agtcattgac
tgaatacctt caaaatgtgg aacaaaagaa aagacagttg gaggaatctg 2460tcgatgccct
cagtgaagaa ctagtccagc ttcgagcaca agagaaagtc catgaaatgg 2520aaaaggagca
cttaaataag gttcagactg caaatgaagt taagcaagct gttgaacagc 2580agatccagag
ccatagagaa actcatcaaa aacagatcag tagtttgaga gatgaagtag 2640aagcaaaagc
aaaacttatt actgatcttc aagaccaaaa ccagaaaatg atgttagagc 2700aggaacgtct
aagagtagaa catgagaagt tgaaagccac agatcaggaa aagagcagaa 2760aactacatga
acttacggtt atgcaagata gacgagaaca agcaagacaa gacttgaagg 2820gtttggaaga
gacagtggca aaagaacttc agactttaca caacctgcgc aaactctttg 2880ttcaggacct
ggctacaaga gttaaaaaga gtgctgagat tgattctgat gacaccggag 2940gcagcgctgc
tcagaagcaa aaaatctcct ttcttgaaaa taatcttgaa cagctcacta 3000aagtgcacaa
acagttggta cgtgataatg cagatctccg ctgtgaactt cctaagttgg 3060aaaagcgact
tcgagctaca gctgagagag tgaaagcttt ggaatcagca ctgaaagaag 3120ctaaagaaaa
tgcatctcgt gatcgcaaac gctatcagca agaagtagat cgcataaagg 3180aagcagtcag
gtcaaagaat atggccagaa gagggcattc tgcacagatt gctaaaccta 3240ttcgtcccgg
gcaacatcca gcagcttctc caactcaccc aagtgcaatt cgtggaggag 3300gtgcatttgt
tcagaacagc cagccagtgg cagtgcgagg tggaggaggc aaacaagtgt 3360aatcgtttat
acatacccac aggtgttaaa aagtaatcga agtacgaaga ggacatggta 3420tcaagcagtc
attcaatgac tataacctct actcccttgg gattgtagaa ttataacttt 3480taaaaaaaat
gtataaatta tacctggcct gtacagctgt ttcctaccta ctcttcttgt 3540aaactctgct
gcttcccaac acaactagag tgcaattttg gcatcttagg agggaaaaag 3600gacagtttac
aactgtggcc ctatttatta cacagtttgt ctatcgtgtc ttaaatttag 3660tctttactgt
gccaagctaa ctgtacctta taggactgta ctttttgtat tttttgtgta 3720tgtttatttt
ttaatctcag tttaaattac ctagctgcta ctgcttcttg tttttctttt 3780cctattaaaa
cgtcttcctt tttttttctt aagagaaaat ggaacattta ggttaaatgt 3840ctttaaattt
taccacttaa caacactaca tgcccataaa atatatccag tcagtactgt 3900attttaaaat
cccttgaaat gatgatatca gggttaaaat tacttgtatt gtttctgaag 3960tttgctcctg
aaaactactg tttgagcact gaaacgttac aaatgcctaa taggcatttg 4020agactgagca
aggctacttg ttatctcatg aaatgcctgt tgccgagtta ttttgaatag 4080aaatatttta
aagtatcaaa agcagatctt agtttaaggg agtttggaaa aggaattata 4140tttctctttt
tcctgattct gtactcaaca agtcttgatg gaattaaaat actctgcttt 4200attctggtga
gcctgctagc taatataagt attggacagg taataatttg tcatctttaa 4260tattagtaaa
atgaattaag atattatagg attaaacata attttatacg gttagtactt 4320tattggccga
cctaaattta tagcgtgtgg aaattgagaa aaatgaagaa acaggacaga 4380tatatgatga
attaaaaata tatataggtc aattttggtc tgaaatccct gaggtgtttt 4440taacctgcta
cactaatttg tacactaatt tatttcttta gtctagaaat agtaaattgt 4500ttgcaagtca
ctaataatca ttagataaat tattttcttg gccatagccg ataattttgt 4560aatcagtact
aagtgtatac gtatttttgc cactttttcc tcagatgatt aaagtaagtc 4620aacagcttat
tttaggaaac tgtaaaagta atagggaaag agatttcact atttgcttca 4680tcagtggtag
gggggcggtg actgcaactg tgttagcaga aattcacaga gaatggggat 4740ttaaggttag
cagagaaact tggaaagttc tgtgttagga tcttgctggc agaattaact 4800ttttgcaaaa
gttttataca cagatatttg tattaaattt ggagccatag tcagaagact 4860cagatcataa
ttggcttatt tttctatttc cgtaactatt gtaatttcca cttttgtaat 4920aattttgatt
taaaatataa atttatttat ttattttttt aatagtcaaa aatctttgct 4980gttgtagtct
gcaacctcta aaatgattgt gttgctttta ggattgatca gaagaaacac 5040tccaaaaatt
gagatgaaat gttggtgcag ccagttataa gtaatatagt taacaagcaa 5100aaaaagtgct
gccacctttt atgatgattt tctaaatgga gaaacatttg gctgcatcca 5160catagacctt
tatgttttgt tttcagttga aaacttgcct cctttggcaa cattcgtaaa 5220tgaagcagaa
tttttttttc tcttttttcc aaatatgtta gttttgttct tgtaagatgt 5280atcatgggta
ttggtgctgt gtaatgaaca acgaatttta attagcatgt ggttcagaat 5340atacaatgtt
aggtttttaa aaagtatctt gatggttctt ttctatttat aatttcagac 5400tttcataaag
tgtaccaaga atttcataaa tttgttttca gtgaactgct ttttgctatg 5460gtaggtcatt
aaacacagca cttactctta aaaatgaaaa tttctgatca tctaggatat 5520tgacacattt
caatttgcag tgtctttttg actggatata ttaacgttcc tctgaatggc 5580attgatagat
ggttcagaag agaaactcaa tgaaataaag agaatattta ttcatggcga 5640ttaattaaat
tatttgccta acttaagaaa actactgtgc gtaactctca gtttgtgctt 5700aactccattt
gacatgaggt gacagaagag agtctgagtc tacctgtgga atatgttggt 5760ttattttcag
tgcttgaaga tacattcaca aatacttggt ttgggaagac accgtttaat 5820tttaagttaa
cttgcatgtt gtaaatgcgt tttatgttta aataaagagg aaaatttttt 5880gaaatgtaaa
aaaaaaaaaa aaaaa 590530963PRTHomo
sapiensmisc_featurekinesin-1 heavy chain (NP_004512.1) 30Met Ala Asp Leu
Ala Glu Cys Asn Ile Lys Val Met Cys Arg Phe Arg 1 5
10 15 Pro Leu Asn Glu Ser Glu Val Asn Arg
Gly Asp Lys Tyr Ile Ala Lys 20 25
30 Phe Gln Gly Glu Asp Thr Val Val Ile Ala Ser Lys Pro Tyr
Ala Phe 35 40 45
Asp Arg Val Phe Gln Ser Ser Thr Ser Gln Glu Gln Val Tyr Asn Asp 50
55 60 Cys Ala Lys Lys Ile
Val Lys Asp Val Leu Glu Gly Tyr Asn Gly Thr 65 70
75 80 Ile Phe Ala Tyr Gly Gln Thr Ser Ser Gly
Lys Thr His Thr Met Glu 85 90
95 Gly Lys Leu His Asp Pro Glu Gly Met Gly Ile Ile Pro Arg Ile
Val 100 105 110 Gln
Asp Ile Phe Asn Tyr Ile Tyr Ser Met Asp Glu Asn Leu Glu Phe 115
120 125 His Ile Lys Val Ser Tyr
Phe Glu Ile Tyr Leu Asp Lys Ile Arg Asp 130 135
140 Leu Leu Asp Val Ser Lys Thr Asn Leu Ser Val
His Glu Asp Lys Asn 145 150 155
160 Arg Val Pro Tyr Val Lys Gly Cys Thr Glu Arg Phe Val Cys Ser Pro
165 170 175 Asp Glu
Val Met Asp Thr Ile Asp Glu Gly Lys Ser Asn Arg His Val 180
185 190 Ala Val Thr Asn Met Asn Glu
His Ser Ser Arg Ser His Ser Ile Phe 195 200
205 Leu Ile Asn Val Lys Gln Glu Asn Thr Gln Thr Glu
Gln Lys Leu Ser 210 215 220
Gly Lys Leu Tyr Leu Val Asp Leu Ala Gly Ser Glu Lys Val Ser Lys 225
230 235 240 Thr Gly Ala
Glu Gly Ala Val Leu Asp Glu Ala Lys Asn Ile Asn Lys 245
250 255 Ser Leu Ser Ala Leu Gly Asn Val
Ile Ser Ala Leu Ala Glu Gly Ser 260 265
270 Thr Tyr Val Pro Tyr Arg Asp Ser Lys Met Thr Arg Ile
Leu Gln Asp 275 280 285
Ser Leu Gly Gly Asn Cys Arg Thr Thr Ile Val Ile Cys Cys Ser Pro 290
295 300 Ser Ser Tyr Asn
Glu Ser Glu Thr Lys Ser Thr Leu Leu Phe Gly Gln 305 310
315 320 Arg Ala Lys Thr Ile Lys Asn Thr Val
Cys Val Asn Val Glu Leu Thr 325 330
335 Ala Glu Gln Trp Lys Lys Lys Tyr Glu Lys Glu Lys Glu Lys
Asn Lys 340 345 350
Ile Leu Arg Asn Thr Ile Gln Trp Leu Glu Asn Glu Leu Asn Arg Trp
355 360 365 Arg Asn Gly Glu
Thr Val Pro Ile Asp Glu Gln Phe Asp Lys Glu Lys 370
375 380 Ala Asn Leu Glu Ala Phe Thr Val
Asp Lys Asp Ile Thr Leu Thr Asn 385 390
395 400 Asp Lys Pro Ala Thr Ala Ile Gly Val Ile Gly Asn
Phe Thr Asp Ala 405 410
415 Glu Arg Arg Lys Cys Glu Glu Glu Ile Ala Lys Leu Tyr Lys Gln Leu
420 425 430 Asp Asp Lys
Asp Glu Glu Ile Asn Gln Gln Ser Gln Leu Val Glu Lys 435
440 445 Leu Lys Thr Gln Met Leu Asp Gln
Glu Glu Leu Leu Ala Ser Thr Arg 450 455
460 Arg Asp Gln Asp Asn Met Gln Ala Glu Leu Asn Arg Leu
Gln Ala Glu 465 470 475
480 Asn Asp Ala Ser Lys Glu Glu Val Lys Glu Val Leu Gln Ala Leu Glu
485 490 495 Glu Leu Ala Val
Asn Tyr Asp Gln Lys Ser Gln Glu Val Glu Asp Lys 500
505 510 Thr Lys Glu Tyr Glu Leu Leu Ser Asp
Glu Leu Asn Gln Lys Ser Ala 515 520
525 Thr Leu Ala Ser Ile Asp Ala Glu Leu Gln Lys Leu Lys Glu
Met Thr 530 535 540
Asn His Gln Lys Lys Arg Ala Ala Glu Met Met Ala Ser Leu Leu Lys 545
550 555 560 Asp Leu Ala Glu Ile
Gly Ile Ala Val Gly Asn Asn Asp Val Lys Gln 565
570 575 Pro Glu Gly Thr Gly Met Ile Asp Glu Glu
Phe Thr Val Ala Arg Leu 580 585
590 Tyr Ile Ser Lys Met Lys Ser Glu Val Lys Thr Met Val Lys Arg
Cys 595 600 605 Lys
Gln Leu Glu Ser Thr Gln Thr Glu Ser Asn Lys Lys Met Glu Glu 610
615 620 Asn Glu Lys Glu Leu Ala
Ala Cys Gln Leu Arg Ile Ser Gln His Glu 625 630
635 640 Ala Lys Ile Lys Ser Leu Thr Glu Tyr Leu Gln
Asn Val Glu Gln Lys 645 650
655 Lys Arg Gln Leu Glu Glu Ser Val Asp Ala Leu Ser Glu Glu Leu Val
660 665 670 Gln Leu
Arg Ala Gln Glu Lys Val His Glu Met Glu Lys Glu His Leu 675
680 685 Asn Lys Val Gln Thr Ala Asn
Glu Val Lys Gln Ala Val Glu Gln Gln 690 695
700 Ile Gln Ser His Arg Glu Thr His Gln Lys Gln Ile
Ser Ser Leu Arg 705 710 715
720 Asp Glu Val Glu Ala Lys Ala Lys Leu Ile Thr Asp Leu Gln Asp Gln
725 730 735 Asn Gln Lys
Met Met Leu Glu Gln Glu Arg Leu Arg Val Glu His Glu 740
745 750 Lys Leu Lys Ala Thr Asp Gln Glu
Lys Ser Arg Lys Leu His Glu Leu 755 760
765 Thr Val Met Gln Asp Arg Arg Glu Gln Ala Arg Gln Asp
Leu Lys Gly 770 775 780
Leu Glu Glu Thr Val Ala Lys Glu Leu Gln Thr Leu His Asn Leu Arg 785
790 795 800 Lys Leu Phe Val
Gln Asp Leu Ala Thr Arg Val Lys Lys Ser Ala Glu 805
810 815 Ile Asp Ser Asp Asp Thr Gly Gly Ser
Ala Ala Gln Lys Gln Lys Ile 820 825
830 Ser Phe Leu Glu Asn Asn Leu Glu Gln Leu Thr Lys Val His
Lys Gln 835 840 845
Leu Val Arg Asp Asn Ala Asp Leu Arg Cys Glu Leu Pro Lys Leu Glu 850
855 860 Lys Arg Leu Arg Ala
Thr Ala Glu Arg Val Lys Ala Leu Glu Ser Ala 865 870
875 880 Leu Lys Glu Ala Lys Glu Asn Ala Ser Arg
Asp Arg Lys Arg Tyr Gln 885 890
895 Gln Glu Val Asp Arg Ile Lys Glu Ala Val Arg Ser Lys Asn Met
Ala 900 905 910 Arg
Arg Gly His Ser Ala Gln Ile Ala Lys Pro Ile Arg Pro Gly Gln 915
920 925 His Pro Ala Ala Ser Pro
Thr His Pro Ser Ala Ile Arg Gly Gly Gly 930 935
940 Ala Phe Val Gln Asn Ser Gln Pro Val Ala Val
Arg Gly Gly Gly Gly 945 950 955
960 Lys Gln Val 315842DNAHomo sapiensmisc_featureCCDC6
(NM_005436.4) 31agtgcaatac tgcccaagcc cgggcggggt ctctgttctc tggcagagga
ggtcccttgg 60cagcgggaag cgccctctct ttctctcgcc gccgctccga gtctgcgccc
tggtgccagg 120cgctcagctc ggcgctcccc tgtgctcgcc cggcgcccac tcattcgcag
cccggccttc 180gtcgccgccg cctccctgct gctcctcctc ctttccccag cccgccgcgg
ccatggcgga 240cagcgccagc gagagcgaca cggacggggc ggggggcaac agcagcagct
cggccgccat 300gcagtcgtcc tgctcgtcga cctcgggcgg cggcggtggc ggcgggggag
gcggcggcgg 360tgggaagtcg gggggcattg tcatctcgcc gttccgcctg gaggagctca
ccaaccgcct 420ggcctcgctg cagcaagaga acaaggtgct gaagatagag ctggagacct
acaaactgaa 480gtgcaaggca ctgcaggagg agaaccgcga cctgcgcaaa gccagcgtga
ccatccaagc 540cagggctgag caggaagaag aattcattag taacacttta ttcaagaaaa
ttcaggcttt 600gcagaaggag aaagaaaccc ttgctgtaaa ttatgagaaa gaagaagaat
tcctcactaa 660tgagctctcc agaaaattga tgcagttgca gcatgagaaa gccgaactag
aacagcatct 720tgaacaagag caggaatttc aggtcaacaa actgatgaag aaaattaaaa
aactggagaa 780tgacaccatt tctaagcaac ttacattaga acagttgaga cgggagaaga
ttgaccttga 840aaatacattg gaacaagaac aagaagcact agttaatcgc ctctggaaaa
ggatggataa 900gcttgaagct gaaaagcgaa tcctgcagga aaaattagac cagcccgtct
ctgctccacc 960atcgcctaga gatatctcca tggagattga ttctccagaa aatatgatgc
gtcacatcag 1020gtttttaaag aatgaagtgg aacggctgaa gaagcaactg agagctgctc
agttacagca 1080ttcagagaaa atggcacagt atctggagga ggaacgtcac atgagagaag
agaacttgag 1140gctccagagg aagctgcaga gggagatgga gagaagagaa gccctctgtc
gacagctctc 1200cgagagtgag tccagcttag aaatggacga cgaaaggtat tttaatgaga
tgtctgcaca 1260aggattaaga cctcgcactg tgtccagccc gatcccttac acaccttctc
cgagttcaag 1320caggcctata tcacctggtc tatcatatgc aagtcacacg gttggtttca
cgccaccaac 1380ttcactgact agagctggaa tgtcttatta caattccccg ggtcttcacg
tgcagcacat 1440gggaacatcc catggtatca caaggccttc accacggaga agcaacagtc
ctgacaaatt 1500caaacggccc acgccgcctc catctcccaa cacacagacc ccagtccagc
cacctccgcc 1560tccacctccg ccacccatgc agcccacggt cccctcagca gccacctcgc
agcctactcc 1620ttcgcaacat tcggcgcacc cctcctccca gccttaatgc atgagcttag
tctgaatttc 1680aagttgggac tcatccaatg gagccgtcta ctcaacgcca aaggcttcct
tctctggcat 1740atttggatat gacttatttg cactgaggtt atctaggctt cactatccat
tgtgttgtaa 1800atgtttgtca gaaatgcagc cagtgttgtg ggtctacaac actaaccaga
cgactttttc 1860catcagtgtt ttacttgaat cttcatgtac gtccattccc tggctggaac
cttcgctgtt 1920tggtatttgg tatttcagca gcagtgtgca atttttgctt ggcccagagc
ttcattctcc 1980tggcttttag gtttgtaaaa gaaaaaggga tatctttttt atattttttt
ccatgaatct 2040gcagaaaatt actgagctgt tgttaccctc ctctcattat aatagtgttt
accaaacata 2100ccaataattc agcactacaa ttcagacctt tgaaaatctg gctttcagtg
tagaacagaa 2160agttagatga atcagtgccc aagacatatt ttctgtttaa cagaactttc
tacagataca 2220ttttttacag gttattttca ttgtgttatt gacatccatg tctctcgtaa
aacagatggc 2280ccaaagtaat gaatcatgtg gctgtacctt ctccacataa atgggatgga
taattatcgt 2340atattaagat gtgattctct tttttatcct taatgttaat ctacttaacc
tggccccctc 2400taacatgagt cgataaatgt tgtcctactc accggtggtt tcaatggcta
attagaatgt 2460gttatttgat ttctgctgca gaaggcagtg tgattgtaac aaaaacaatg
cggcttcccc 2520ctttcgtact tcatttgtgt tctcttaaaa tagagtttga acaaatattt
taaaggtgca 2580aaataccatt agaaaatact atttgaaatg gacattatcg cattatcttg
gcataatggc 2640cagaaaatat tgtattgctt ggcagaaaag aaaataaggt ctaaaggaaa
gtagcacatt 2700agcattgatg gctgttcatt tcacccagta taagcaagtg cagtgtacaa
agaagtatat 2760tctgaataca ttatttccat tcatttagca caaataaatc atttggtttc
actttgcagt 2820ggaacactga gtcactcttt tcttaacacg tgcaacatct taatttttgt
ttttcagcag 2880ttgctgtttt gtactttggt agtaaagtga tttttaccac ctgtgtttgc
atatttatat 2940atgctgtgga tgaaaataac ttactagaga atgtatattt tatgacaaga
atgtgtatct 3000gttggatata atcagagaac tgaaaagtaa tttatcagta atttttaaga
gtccatgttt 3060tgtgacaacc atctctaata gccaactctt tattaaacac actcctaaaa
ataaggaacc 3120atgacattgt agatatttaa tattgtacag tatagaaacc tccatttttg
ccttcgaatg 3180catatttaag agttaacaga atgaaaaaaa aaagtcttgt tggataatag
tgtttgacta 3240gcgttttaag aacttgagag taaaagcaac aataagattt tttcacctct
tcctgcttcc 3300acccccaaac tgagaacatc actcaattgt ttggaagaaa ctgtaggtct
atataaattt 3360tatttataat gtatgtgtaa tatacataat cataatacag ttctcagatg
cagggaagaa 3420gtttggcatt taatcattga ggctttaggt ttttgatgtg atcagactgg
gccatgtcaa 3480acccggaatt ttcaccaaca gttcactcac cctcctggta cattgccatt
ccaaggaatt 3540ctgagagtag gcaaacaaat tttgccttca tggtacagtt ctcagttttt
cttataggag 3600aaatatggta tatgtttata agaatctttt atgagattat agatttcaat
gctgtggata 3660gtgtcttgca cccaaacaag aaagtccata atggaatgat cttccctcag
cttcctatcg 3720atttagttac ctcttgaaag cacaaaaatt aaaacattgc catatgttga
atttttaaaa 3780agcacttgga gtgagcgaac atttcctgat aaatgccttt tagagatagg
ttcttgatat 3840tcagacatct gcagaaatgt tctggttccc aaagtcattt cacttcgaaa
taaaacacag 3900ctccttcaaa cagcactttt tccacataaa tctagttgcc tctccctgtg
gacattcaga 3960actgatagaa caaacactac tcttttgaat ttgatggttc gtgtccttta
aagtgtttga 4020ggacctatgc agagcctgta acacttgggt agtacctgct aggacaattt
cttggcaatt 4080gtcttactac tagggatcag taagatttag attctgagcc cataatggca
acagccccct 4140cacctatggg aagctgactt ccctcagtcg ggcacttctc atgggggctg
aacatggttc 4200ctgccattct gttacccact ctcccaggtg agccctggat tggctcccag
aaggcctttg 4260taaaatcagt agccgtcctg caggcaggtg ggagcaacag gggcttcagt
agcttcattt 4320tcctgtcttg cagacagaga cccttggcta ccactgtgct gctaatagga
taagtactct 4380gttgccagat taccatgcct tttatacaaa accaaattaa cttacctaat
acctgacacc 4440tctttgggct ctgaactgct ttctctcatc aagcatgcta gcactctaga
cagaattcta 4500gaaatttggc agatagtgga agcctttaat tgaacttact ccttcgttga
ctgaaaggag 4560ttttaaattc tgagctcctg agatactgac tagcaaccat ggaatgaatg
tgtgaccaga 4620aagtggcttt gacaccaagt gctactgtcc ctttgtaatt ggcttctaac
agaattcaac 4680cagaaataat tgataatgtg aatttttgtt aattgttcac ttgtaggaaa
atagaacatg 4740tatcaccctt tgttaggtag acatgaactt ttcctgcaca aagccttgct
tttagagaat 4800gcccaataag gcaagaaaaa gcatagtaac ttgtgctttg agagctcaat
atttgtatct 4860tatcagtaca gaagaaatat ttctgtgtaa cttgatcttc tgtctagtac
ttgtcttata 4920ggtaaccaac actgaaaact ttgtagtgat gactaccaaa gaaatacata
gtaaaacaac 4980cttttatttc caaattgtta aagagccagc cattgatgct gctacatgag
ttccatgctc 5040aagagccatt gtaagagatt aaggggtttc taggtttttg gtgatttttt
gtttgttttt 5100ttctttgttt tttagggttt ttttttcttc tttaattttt tgattaaaac
atacacacag 5160ctgttagcat aaagtcgtgg ggggcatttt ctggaatgct cagcagttct
gattaactgc 5220caagcccagg ttgcctctca tgaggcaact gaaaaaatcc tgtgtcttga
tagcatgggt 5280gctgtgtgtg tgcatgtgtg tgtctgcatt catgccttaa ctcgggttac
tgcacaactt 5340tagttcttga cttagtctgc accgtcatct agattgtatt gtacatctcg
gtctgaactt 5400catcctggca aaaacaaagt tgcaggcaca acagtttaag aatgcattcc
tccagaagag 5460tatctggtca ggttgacccc tgagccttct ttggacttga tttggaactt
agcctggaaa 5520gcgaaagtgg actgtccaac agaaagatgt caacaaggaa aagaggagag
ccaagcgcta 5580gcatgccttt tgcctctgca tatctgtgca cactgtatgt tgttcatgat
agcttgtcta 5640caacttgact aggttggagt tctggtaata gtggcaatct tgacattctt
ggtcagagtt 5700tagagagatg taagactttc aattaatgtc ttatttactc ctttatgttg
attagtcttt 5760gatacatgtg ctgaatcaga aacctaaata aagataattt tttaaaatgt
acctcttgag 5820ccttaaaaaa aaaaaaaaaa aa
584232474PRTHomo sapiensmisc_featureCCDC6 (NP_005427.2) 32Met
Ala Asp Ser Ala Ser Glu Ser Asp Thr Asp Gly Ala Gly Gly Asn 1
5 10 15 Ser Ser Ser Ser Ala Ala
Met Gln Ser Ser Cys Ser Ser Thr Ser Gly 20
25 30 Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly
Gly Gly Lys Ser Gly Gly 35 40
45 Ile Val Ile Ser Pro Phe Arg Leu Glu Glu Leu Thr Asn Arg
Leu Ala 50 55 60
Ser Leu Gln Gln Glu Asn Lys Val Leu Lys Ile Glu Leu Glu Thr Tyr 65
70 75 80 Lys Leu Lys Cys Lys
Ala Leu Gln Glu Glu Asn Arg Asp Leu Arg Lys 85
90 95 Ala Ser Val Thr Ile Gln Ala Arg Ala Glu
Gln Glu Glu Glu Phe Ile 100 105
110 Ser Asn Thr Leu Phe Lys Lys Ile Gln Ala Leu Gln Lys Glu Lys
Glu 115 120 125 Thr
Leu Ala Val Asn Tyr Glu Lys Glu Glu Glu Phe Leu Thr Asn Glu 130
135 140 Leu Ser Arg Lys Leu Met
Gln Leu Gln His Glu Lys Ala Glu Leu Glu 145 150
155 160 Gln His Leu Glu Gln Glu Gln Glu Phe Gln Val
Asn Lys Leu Met Lys 165 170
175 Lys Ile Lys Lys Leu Glu Asn Asp Thr Ile Ser Lys Gln Leu Thr Leu
180 185 190 Glu Gln
Leu Arg Arg Glu Lys Ile Asp Leu Glu Asn Thr Leu Glu Gln 195
200 205 Glu Gln Glu Ala Leu Val Asn
Arg Leu Trp Lys Arg Met Asp Lys Leu 210 215
220 Glu Ala Glu Lys Arg Ile Leu Gln Glu Lys Leu Asp
Gln Pro Val Ser 225 230 235
240 Ala Pro Pro Ser Pro Arg Asp Ile Ser Met Glu Ile Asp Ser Pro Glu
245 250 255 Asn Met Met
Arg His Ile Arg Phe Leu Lys Asn Glu Val Glu Arg Leu 260
265 270 Lys Lys Gln Leu Arg Ala Ala Gln
Leu Gln His Ser Glu Lys Met Ala 275 280
285 Gln Tyr Leu Glu Glu Glu Arg His Met Arg Glu Glu Asn
Leu Arg Leu 290 295 300
Gln Arg Lys Leu Gln Arg Glu Met Glu Arg Arg Glu Ala Leu Cys Arg 305
310 315 320 Gln Leu Ser Glu
Ser Glu Ser Ser Leu Glu Met Asp Asp Glu Arg Tyr 325
330 335 Phe Asn Glu Met Ser Ala Gln Gly Leu
Arg Pro Arg Thr Val Ser Ser 340 345
350 Pro Ile Pro Tyr Thr Pro Ser Pro Ser Ser Ser Arg Pro Ile
Ser Pro 355 360 365
Gly Leu Ser Tyr Ala Ser His Thr Val Gly Phe Thr Pro Pro Thr Ser 370
375 380 Leu Thr Arg Ala Gly
Met Ser Tyr Tyr Asn Ser Pro Gly Leu His Val 385 390
395 400 Gln His Met Gly Thr Ser His Gly Ile Thr
Arg Pro Ser Pro Arg Arg 405 410
415 Ser Asn Ser Pro Asp Lys Phe Lys Arg Pro Thr Pro Pro Pro Ser
Pro 420 425 430 Asn
Thr Gln Thr Pro Val Gln Pro Pro Pro Pro Pro Pro Pro Pro Pro 435
440 445 Met Gln Pro Thr Val Pro
Ser Ala Ala Thr Ser Gln Pro Thr Pro Ser 450 455
460 Gln His Ser Ala His Pro Ser Ser Gln Pro 465
470 333748DNAHomo
sapiensmisc_featureNCOA4 variant 1 (NM_001145260.1) 33agagggcagt
caagggcttc tggctgaccc gagcggagat ctcgcgagac tgtcagacgt 60atggcgagag
gtgtgggagg aagattgtgt tgtcgcgaga actctgcctt tgggccgtag 120gttagtgtgg
ggccgtgtct cagtccaccc aaggtctcct cggatcgcct ggagaggcac 180tcggacctgt
tatgtctgga cacattgctt caacatagaa cgcacatgaa caatgtggag 240gtctaggctg
gaatgggggc ccagttgacc acttttgctc tagctggagc agtgaggaga 300atgaatacct
tccaagacca gagtggcagc tccagtaata gagaacccct tttgaggtgt 360agtgatgcac
ggagggactt ggagcttgct attggtggag ttctccgggc tgaacagcaa 420attaaagata
acttgcgaga ggtcaaagct cagattcaca gttgcataag ccgtcacctg 480gaatgtctta
gaagccgtga ggtatggctg tatgaacagg tggaccttat ttatcagctt 540aaagaggaga
cacttcaaca gcaggctcag cagctctact cgttattggg ccagttcaat 600tgtcttactc
atcaactgga gtgtacccaa aacaaagatc tagccaatca agtctctgtg 660tgcctggaga
gactgggcag tttgaccctt aagcctgaag attcaactgt cctgctcttt 720gaagctgaca
caattactct gcgccagacc atcaccacat ttgggtctct caaaaccatt 780caaattcctg
agcacttgat ggctcatgct agttcagcaa atattgggcc cttcctggag 840aagagaggct
gtatctccat gccagagcag aagtcagcat ccggtattgt agctgtccct 900ttcagcgaat
ggctccttgg aagcaaacct gccagtggtt atcaagctcc ttacataccc 960agcaccgacc
cccaggactg gcttacccaa aagcagacct tggagaacag tcagacttct 1020tccagagcct
gcaatttctt caataatgtc gggggaaacc taaagggctt agaaaactgg 1080ctcctcaaga
gtgaaaaatc aagttatcaa aagtgtaaca gccattccac tactagttct 1140ttctccattg
aaatggaaaa ggttggagat caagagcttc ctgatcaaga tgagatggac 1200ctatcagatt
ggctagtgac tccccaggaa tcccataagc tgcggaagcc tgagaatggc 1260agtcgtgaaa
ccagtgagaa gtttaagctc ttattccagt cctataatgt gaatgattgg 1320cttgtcaaga
ctgactcctg taccaactgt cagggaaacc agcccaaagg tgtggagatt 1380gaaaacctgg
gcaatctgaa gtgcctgaat gaccacttgg aggccaagaa accattgtcc 1440acccccagca
tggttacaga ggattggctt gtccagaacc atcaggaccc atgtaaggta 1500gaggaggtgt
gcagagccaa tgagccctgc acaagctttg cagagtgtgt gtgtgatgag 1560aattgtgaga
aggaggctct gtataagtgg cttctgaaga aagaaggaaa ggataaaaat 1620gggatgcctg
tggaacccaa acctgagcct gagaagcata aagattccct gaatatgtgg 1680ctctgtccta
gaaaagaagt aatagaacaa actaaagcac caaaggcaat gactccttct 1740agaattgctg
attccttcca agtcataaag aacagcccct tgtcggagtg gcttatcagg 1800cccccataca
aagaaggaag tcccaaggaa gtgcctggta ctgaagacag agctggcaaa 1860cagaagttta
aaagccccat gaatacttcc tggtgttcct ttaacacagc tgactgggtc 1920ctgccaggaa
agaagatggg caacctcagc cagttatctt ctggagaaga caagtggctg 1980cttcgaaaga
aggcccagga agtattactt aattcacctc tacaggagga acataacttc 2040cccccagacc
attatggcct ccctgcagtt tgtgatctct ttgcctgtat gcagcttaaa 2100gttgataaag
agaagtggtt atatcgaact cctctacagg catacttcaa aatgaacttt 2160caagatgtaa
ccgttgggaa ttttcagatc ccatgtggat tctagtagtt tatataccta 2220cctcgaagat
gtgaaggaat ggacaagagt tgagcagcct ttctgctgat tatcacacat 2280catgagctga
gtgactgcag cttgccaaat ctttgtgttt ctgggtctga ccaattagct 2340tagttcttct
cctgcctaat tttgaactag taaagcaaag tgagtcatca gattatgagt 2400tactgtttaa
aagaaaaatg ctgtttattc atgctgaggt gattcagttc cctccttctt 2460acagaagtat
tttaattcac cccacactag aaatgcagca tctttgtgga cgtctttttc 2520acaagcctcc
aaggctcctt agattgggtc gttactaaaa gtacattaaa acactcttgt 2580ttatcgaagt
atattgatgt attctaaagc tagtaaactt ccctaacgtt taattgccct 2640acagatgctt
ctcttgctgt gggttttctt ttgttagtgg tctgaaataa ttattttcct 2700gttctattaa
tacatagtgt attttgcaca aaaaaattaa cctggtcaat agtgattacc 2760aaaatatata
ttaataatct tggcaatttt tgacattaat tatgaaacat tttagcccac 2820gttagttcta
cattattctt cacttaaact cagctactgc aaattttgtc tttctgtaaa 2880tgttattaaa
atatccagtg agctctttag aaggactcag tattatttca agactatttt 2940tgaggtaatt
ctagcctttt aaaatattct acagacctac ggggcttaaa agaaccccag 3000taccgactaa
gcaaataggc aaaagacatg ttggaaatgt agtatagtac ttgaaacagt 3060cactatcata
gggataattg gtgcatcctg tgtaaatgga agctgagctt gacacctggt 3120gcttttaagt
agggataaag tcatcctctc actgcaagca cagcatacct gtacctccaa 3180aagtgacgtt
ttagtgaaca ggccgttttc aacacttgtg ccttggggtg ttcattgaag 3240ctttgtgaaa
actactgatg ttttctcagt ctccttaaag ttacgtccat gctttaaaat 3300gtctgtgtag
gagagaagtg gggtttataa tgttttctct aagatatctt tgctgctttc 3360cagactttga
aactattaag cttcttaact gcctcttacc ggaaatactt ctggggaaac 3420ttcatggtcc
caaaatgtca ttgccataca gcttcactag agttctttga accacagctg 3480aaaagagctt
tgtattattt tttaattccc tccccagata tcatttagga gtattatata 3540aaggtggtgg
gcaaaaacaa tgtaaggagc ctttccagtt atcttgagtt gcagctctgt 3600agtttcttga
ggccaaacac actgtatttt acaagtcaaa atataattta cattaatcac 3660tatgttaatg
agtatgtaaa acattctttt gcattgatga attttgtatc tgcttccatt 3720aaaagcataa
cagccataaa aaaaaaaa
3748343659DNAHomo sapiensmisc_featureNCOA4 variant 2 (NM_001145261.1)
34agagggcagt caagggcttc tggctgaccc gagcggagat ctcgcgagac tgtcagacgt
60atggcgagag gtgtgggagg aagattgtgt tgtcgcgaga actctgcctt tgggccgtag
120gttagtgtgg ggccgtgtct cagtccaccc aaggtctcct cggatcgcct ggagaggcac
180tcggacctgt tatgtctgga cacattgctt caacatagaa cgcacatgaa caatgtggag
240gtctaggctg gaatgggggc ccagttgacc acttttgctc tagctggagc agtgaggaga
300atgaatacct tccaagacca gagtggcagc tccagtaata gagaacccct tttgaggtgt
360agtgatgcac ggagggactt ggagcttgct attggtggag ttctccgggc tgaacagcaa
420attaaagata acttgcgaga ggtcaaagct cagattcaca gttgcataag ccgtcacctg
480gaatgtctta gaagccgtga ggtatggctg tatgaacagg tggaccttat ttatcagctt
540aaagaggaga cacttcaaca gcaggctcag cagctctact cgttattggg ccagttcaat
600tgtcttactc atcaactgga gtgtacccaa aacaaagatc tagccaatca agtctctgtg
660tgcctggaga gactgggcag tttgaccctt aagcctgaag attcaactgt cctgctcttt
720gaagctgaca caattactct gcgccagacc atcaccacat ttgggtctct caaaaccatt
780caaattcctg agcacttgat ggctcatgct agttcagcaa atattgggcc cttcctggag
840aagagaggct gtatctccat gccagagcag aagtcagcat ccggtattgt agctgtccct
900ttcagcgaat ggctccttgg aagcaaacct gccagtggtt atcaagctcc ttacataccc
960agcaccgacc cccaggactg gcttacccaa aagcagacct tggagaacag tcagacttct
1020tccagagcct gcaatttctt caataatgtc gggggaaacc taaagggctt agaaaactgg
1080ctcctcaaga gtgaaaaatc aagttatcaa aagtgtaaca gccattccac tactagttct
1140ttctccattg aaatggaaaa ggttggagat caagagcttc ctgatcaaga tgagatggac
1200ctatcagatt ggctagtgac tccccaggaa tcccataagc tgcggaagcc tgagaatggc
1260agtcgtgaaa ccagtgagaa gtttaagctc ttattccagt cctataatgt gaatgattgg
1320cttgtcaaga ctgactcctg taccaactgt cagggaaacc agcccaaagg tgtggagatt
1380gaaaacctgg gcaatctgaa gtgcctgaat gaccacttgg aggccaagaa accattgtcc
1440acccccagca tggttacaga ggattggctt gtccagaacc atcaggaccc atgtaaggta
1500gaggaggtgt gcagagccaa tgagccctgc acaagctttg cagagtgtgt gtgtgatgag
1560aattgtgaga aggaggctct gtataagtgg cttctgaaga aagaaggaaa ggataaaaat
1620gggatgcctg tggaacccaa acctgagcct gagaagcata aagattccct gaatatgtgg
1680ctctgtccta gaaaagaagt aatagaacaa actaaagcac caaaggcaat gactccttct
1740agaattgctg attccttcca agtcataaag aacagcccct tgtcggagtg gcttatcagg
1800cccccataca aagaaggaag tcccaaggaa gtgcctggta ctgaagacag agctggcaaa
1860cagaagttta aaagccccat gaatacttcc tggtgttcct ttaacacagc tgactgggtc
1920ctgccaggaa agaagatggg caacctcagc cagttatctt ctggagaaga caagtggctg
1980cttcgaaaga aggcccagga agtattactt aattcacctc tacaggagga acataacttc
2040cccccagacc attatggcct ccctgcagtt tgtgatctct ttgcctgtat gcagcttaaa
2100gttgataaag agaagtggtt atatcgaact cctctacaga tgtgaaggaa tggacaagag
2160ttgagcagcc tttctgctga ttatcacaca tcatgagctg agtgactgca gcttgccaaa
2220tctttgtgtt tctgggtctg accaattagc ttagttcttc tcctgcctaa ttttgaacta
2280gtaaagcaaa gtgagtcatc agattatgag ttactgttta aaagaaaaat gctgtttatt
2340catgctgagg tgattcagtt ccctccttct tacagaagta ttttaattca ccccacacta
2400gaaatgcagc atctttgtgg acgtcttttt cacaagcctc caaggctcct tagattgggt
2460cgttactaaa agtacattaa aacactcttg tttatcgaag tatattgatg tattctaaag
2520ctagtaaact tccctaacgt ttaattgccc tacagatgct tctcttgctg tgggttttct
2580tttgttagtg gtctgaaata attattttcc tgttctatta atacatagtg tattttgcac
2640aaaaaaatta acctggtcaa tagtgattac caaaatatat attaataatc ttggcaattt
2700ttgacattaa ttatgaaaca ttttagccca cgttagttct acattattct tcacttaaac
2760tcagctactg caaattttgt ctttctgtaa atgttattaa aatatccagt gagctcttta
2820gaaggactca gtattatttc aagactattt ttgaggtaat tctagccttt taaaatattc
2880tacagaccta cggggcttaa aagaacccca gtaccgacta agcaaatagg caaaagacat
2940gttggaaatg tagtatagta cttgaaacag tcactatcat agggataatt ggtgcatcct
3000gtgtaaatgg aagctgagct tgacacctgg tgcttttaag tagggataaa gtcatcctct
3060cactgcaagc acagcatacc tgtacctcca aaagtgacgt tttagtgaac aggccgtttt
3120caacacttgt gccttggggt gttcattgaa gctttgtgaa aactactgat gttttctcag
3180tctccttaaa gttacgtcca tgctttaaaa tgtctgtgta ggagagaagt ggggtttata
3240atgttttctc taagatatct ttgctgcttt ccagactttg aaactattaa gcttcttaac
3300tgcctcttac cggaaatact tctggggaaa cttcatggtc ccaaaatgtc attgccatac
3360agcttcacta gagttctttg aaccacagct gaaaagagct ttgtattatt ttttaattcc
3420ctccccagat atcatttagg agtattatat aaaggtggtg ggcaaaaaca atgtaaggag
3480cctttccagt tatcttgagt tgcagctctg tagtttcttg aggccaaaca cactgtattt
3540tacaagtcaa aatataattt acattaatca ctatgttaat gagtatgtaa aacattcttt
3600tgcattgatg aattttgtat ctgcttccat taaaagcata acagccataa aaaaaaaaa
3659353588DNAHomo sapiensmisc_featureNCOA4 variant 3 (NM_001145262.1)
35attgattcaa ttttacactg tgccaggcat tgtggcattc cacacaaatg gtgagaagct
60aaaagtgaga aatttggcac aggtgaagaa ggctgggtaa cacatttgaa agactgctaa
120acaggtcttg catgactggc ctaagtgcaa agtgaagcag cccatcacgc tccagctctc
180caaatcggag ccggcatttc acccatgtga tacaggagca gtgaggagaa tgaatacctt
240ccaagaccag agtggcagct ccagtaatag agaacccctt ttgaggtgta gtgatgcacg
300gagggacttg gagcttgcta ttggtggagt tctccgggct gaacagcaaa ttaaagataa
360cttgcgagag gtcaaagctc agattcacag ttgcataagc cgtcacctgg aatgtcttag
420aagccgtgag gtatggctgt atgaacaggt ggaccttatt tatcagctta aagaggagac
480acttcaacag caggctcagc agctctactc gttattgggc cagttcaatt gtcttactca
540tcaactggag tgtacccaaa acaaagatct agccaatcaa gtctctgtgt gcctggagag
600actgggcagt ttgaccctta agcctgaaga ttcaactgtc ctgctctttg aagctgacac
660aattactctg cgccagacca tcaccacatt tgggtctctc aaaaccattc aaattcctga
720gcacttgatg gctcatgcta gttcagcaaa tattgggccc ttcctggaga agagaggctg
780tatctccatg ccagagcaga agtcagcatc cggtattgta gctgtccctt tcagcgaatg
840gctccttgga agcaaacctg ccagtggtta tcaagctcct tacataccca gcaccgaccc
900ccaggactgg cttacccaaa agcagacctt ggagaacagt cagacttctt ccagagcctg
960caatttcttc aataatgtcg ggggaaacct aaagggctta gaaaactggc tcctcaagag
1020tgaaaaatca agttatcaaa agtgtaacag ccattccact actagttctt tctccattga
1080aatggaaaag gttggagatc aagagcttcc tgatcaagat gagatggacc tatcagattg
1140gctagtgact ccccaggaat cccataagct gcggaagcct gagaatggca gtcgtgaaac
1200cagtgagaag tttaagctct tattccagtc ctataatgtg aatgattggc ttgtcaagac
1260tgactcctgt accaactgtc agggaaacca gcccaaaggt gtggagattg aaaacctggg
1320caatctgaag tgcctgaatg accacttgga ggccaagaaa ccattgtcca cccccagcat
1380ggttacagag gattggcttg tccagaacca tcaggaccca tgtaaggtag aggaggtgtg
1440cagagccaat gagccctgca caagctttgc agagtgtgtg tgtgatgaga attgtgagaa
1500ggaggctctg tataagtggc ttctgaagaa agaaggaaag gataaaaatg ggatgcctgt
1560ggaacccaaa cctgagcctg agaagcataa agattccctg aatatgtggc tctgtcctag
1620aaaagaagta atagaacaaa ctaaagcacc aaaggcaatg actccttcta gaattgctga
1680ttccttccaa gtcataaaga acagcccctt gtcggagtgg cttatcaggc ccccatacaa
1740agaaggaagt cccaaggaag tgcctggtac tgaagacaga gctggcaaac agaagtttaa
1800aagccccatg aatacttcct ggtgttcctt taacacagct gactgggtcc tgccaggaaa
1860gaagatgggc aacctcagcc agttatcttc tggagaagac aagtggctgc ttcgaaagaa
1920ggcccaggaa gtattactta attcacctct acaggaggaa cataacttcc ccccagacca
1980ttatggcctc cctgcagttt gtgatctctt tgcctgtatg cagcttaaag ttgataaaga
2040gaagtggtta tatcgaactc ctctacagat gtgaaggaat ggacaagagt tgagcagcct
2100ttctgctgat tatcacacat catgagctga gtgactgcag cttgccaaat ctttgtgttt
2160ctgggtctga ccaattagct tagttcttct cctgcctaat tttgaactag taaagcaaag
2220tgagtcatca gattatgagt tactgtttaa aagaaaaatg ctgtttattc atgctgaggt
2280gattcagttc cctccttctt acagaagtat tttaattcac cccacactag aaatgcagca
2340tctttgtgga cgtctttttc acaagcctcc aaggctcctt agattgggtc gttactaaaa
2400gtacattaaa acactcttgt ttatcgaagt atattgatgt attctaaagc tagtaaactt
2460ccctaacgtt taattgccct acagatgctt ctcttgctgt gggttttctt ttgttagtgg
2520tctgaaataa ttattttcct gttctattaa tacatagtgt attttgcaca aaaaaattaa
2580cctggtcaat agtgattacc aaaatatata ttaataatct tggcaatttt tgacattaat
2640tatgaaacat tttagcccac gttagttcta cattattctt cacttaaact cagctactgc
2700aaattttgtc tttctgtaaa tgttattaaa atatccagtg agctctttag aaggactcag
2760tattatttca agactatttt tgaggtaatt ctagcctttt aaaatattct acagacctac
2820ggggcttaaa agaaccccag taccgactaa gcaaataggc aaaagacatg ttggaaatgt
2880agtatagtac ttgaaacagt cactatcata gggataattg gtgcatcctg tgtaaatgga
2940agctgagctt gacacctggt gcttttaagt agggataaag tcatcctctc actgcaagca
3000cagcatacct gtacctccaa aagtgacgtt ttagtgaaca ggccgttttc aacacttgtg
3060ccttggggtg ttcattgaag ctttgtgaaa actactgatg ttttctcagt ctccttaaag
3120ttacgtccat gctttaaaat gtctgtgtag gagagaagtg gggtttataa tgttttctct
3180aagatatctt tgctgctttc cagactttga aactattaag cttcttaact gcctcttacc
3240ggaaatactt ctggggaaac ttcatggtcc caaaatgtca ttgccataca gcttcactag
3300agttctttga accacagctg aaaagagctt tgtattattt tttaattccc tccccagata
3360tcatttagga gtattatata aaggtggtgg gcaaaaacaa tgtaaggagc ctttccagtt
3420atcttgagtt gcagctctgt agtttcttga ggccaaacac actgtatttt acaagtcaaa
3480atataattta cattaatcac tatgttaatg agtatgtaaa acattctttt gcattgatga
3540attttgtatc tgcttccatt aaaagcataa cagccataaa aaaaaaaa
3588363562DNAHomo sapiensmisc_featureNCOA4 variant 4 (NM_001145263.1)
36agagggcagt caagggcttc tggctgaccc gagcggagat ctcgcgagac tgtcagacgt
60atggcgagag gtgtgggagg aagattgtgt tgtcgcgaga actctgcctt tgggccgtag
120gttagtgtgg ggccgtgtct cagtccaccc aaggtctcct cggatcgcct ggagaggcac
180tcggacctgg agcagtgagg agaatgaata ccttccaaga ccagagtggc agctccagta
240atagagaacc ccttttgagg tgtagtgatg cacggaggga cttggagctt gctattggtg
300gagttctccg ggctgaacag caaattaaag ataacttgcg agaggtcaaa gctcagattc
360acagttgcat aagccgtcac ctggaatgtc ttagaagccg tgaggtatgg ctgtatgaac
420aggtggacct tatttatcag cttaaagagg agacacttca acagcaggct cagcagctct
480actcgttatt gggccagttc aattgtctta ctcatcaact ggagtgtacc caaaacaaag
540atctagccaa tcaagtctct gtgtgcctgg agagactggg cagtttgacc cttaagcctg
600aagattcaac tgtcctgctc tttgaagctg acacaattac tctgcgccag accatcacca
660catttgggtc tctcaaaacc attcaaattc ctgagcactt gatggctcat gctagttcag
720caaatattgg gcccttcctg gagaagagag gctgtatctc catgccagag cagaagtcag
780catccggtat tgtagctgtc cctttcagcg aatggctcct tggaagcaaa cctgccagtg
840gttatcaagc tccttacata cccagcaccg acccccagga ctggcttacc caaaagcaga
900ccttggagaa cagtcagact tcttccagag cctgcaattt cttcaataat gtcgggggaa
960acctaaaggg cttagaaaac tggctcctca agagtgaaaa atcaagttat caaaagtgta
1020acagccattc cactactagt tctttctcca ttgaaatgga aaaggttgga gatcaagagc
1080ttcctgatca agatgagatg gacctatcag attggctagt gactccccag gaatcccata
1140agctgcggaa gcctgagaat ggcagtcgtg aaaccagtga gaagtttaag ctcttattcc
1200agtcctataa tgtgaatgat tggcttgtca agactgactc ctgtaccaac tgtcagggaa
1260accagcccaa aggtgtggag attgaaaacc tgggcaatct gaagtgcctg aatgaccact
1320tggaggccaa gaaaccattg tccaccccca gcatggttac agaggattgg cttgtccaga
1380accatcagga cccatgtaag gtagaggagg tgtgcagagc caatgagccc tgcacaagct
1440ttgcagagtg tgtgtgtgat gagaattgtg agaaggaggc tctgtataag tggcttctga
1500agaaagaagg aaaggataaa aatgggatgc ctgtggaacc caaacctgag cctgagaagc
1560ataaagattc cctgaatatg tggctctgtc ctagaaaaga agtaatagaa caaactaaag
1620caccaaaggc aatgactcct tctagaattg ctgattcctt ccaagtcata aagaacagcc
1680ccttgtcgga gtggcttatc aggcccccat acaaagaagg aagtcccaag gaagtgcctg
1740gtactgaaga cagagctggc aaacagaagt ttaaaagccc catgaatact tcctggtgtt
1800cctttaacac agctgactgg gtcctgccag gaaagaagat gggcaacctc agccagttat
1860cttctggaga agacaagtgg ctgcttcgaa agaaggccca ggaagtatta cttaattcac
1920ctctacagga ggaacataac ttccccccag accattatgg cctccctgca gtttgtgatc
1980tctttgcctg tatgcagctt aaagttgata aagagaagtg gttatatcga actcctctac
2040agatgtgaag gaatggacaa gagttgagca gcctttctgc tgattatcac acatcatgag
2100ctgagtgact gcagcttgcc aaatctttgt gtttctgggt ctgaccaatt agcttagttc
2160ttctcctgcc taattttgaa ctagtaaagc aaagtgagtc atcagattat gagttactgt
2220ttaaaagaaa aatgctgttt attcatgctg aggtgattca gttccctcct tcttacagaa
2280gtattttaat tcaccccaca ctagaaatgc agcatctttg tggacgtctt tttcacaagc
2340ctccaaggct ccttagattg ggtcgttact aaaagtacat taaaacactc ttgtttatcg
2400aagtatattg atgtattcta aagctagtaa acttccctaa cgtttaattg ccctacagat
2460gcttctcttg ctgtgggttt tcttttgtta gtggtctgaa ataattattt tcctgttcta
2520ttaatacata gtgtattttg cacaaaaaaa ttaacctggt caatagtgat taccaaaata
2580tatattaata atcttggcaa tttttgacat taattatgaa acattttagc ccacgttagt
2640tctacattat tcttcactta aactcagcta ctgcaaattt tgtctttctg taaatgttat
2700taaaatatcc agtgagctct ttagaaggac tcagtattat ttcaagacta tttttgaggt
2760aattctagcc ttttaaaata ttctacagac ctacggggct taaaagaacc ccagtaccga
2820ctaagcaaat aggcaaaaga catgttggaa atgtagtata gtacttgaaa cagtcactat
2880catagggata attggtgcat cctgtgtaaa tggaagctga gcttgacacc tggtgctttt
2940aagtagggat aaagtcatcc tctcactgca agcacagcat acctgtacct ccaaaagtga
3000cgttttagtg aacaggccgt tttcaacact tgtgccttgg ggtgttcatt gaagctttgt
3060gaaaactact gatgttttct cagtctcctt aaagttacgt ccatgcttta aaatgtctgt
3120gtaggagaga agtggggttt ataatgtttt ctctaagata tctttgctgc tttccagact
3180ttgaaactat taagcttctt aactgcctct taccggaaat acttctgggg aaacttcatg
3240gtcccaaaat gtcattgcca tacagcttca ctagagttct ttgaaccaca gctgaaaaga
3300gctttgtatt attttttaat tccctcccca gatatcattt aggagtatta tataaaggtg
3360gtgggcaaaa acaatgtaag gagcctttcc agttatcttg agttgcagct ctgtagtttc
3420ttgaggccaa acacactgta ttttacaagt caaaatataa tttacattaa tcactatgtt
3480aatgagtatg taaaacattc ttttgcattg atgaattttg tatctgcttc cattaaaagc
3540ataacagcca taaaaaaaaa aa
3562373502DNAHomo sapiensmisc_featureNCOA4 variant 5 (NM_005437.3)
37gaactggagt tgccgtgtga cgcgtgggcg ggacgaggcc cgggctcggg gacctttcgc
60actcgggtca ggggtaaagc agcctgtcgc ttgccgggca gctggtgagt cggtgacctg
120gcctgtgagg agcagtgagg agaatgaata ccttccaaga ccagagtggc agctccagta
180atagagaacc ccttttgagg tgtagtgatg cacggaggga cttggagctt gctattggtg
240gagttctccg ggctgaacag caaattaaag ataacttgcg agaggtcaaa gctcagattc
300acagttgcat aagccgtcac ctggaatgtc ttagaagccg tgaggtatgg ctgtatgaac
360aggtggacct tatttatcag cttaaagagg agacacttca acagcaggct cagcagctct
420actcgttatt gggccagttc aattgtctta ctcatcaact ggagtgtacc caaaacaaag
480atctagccaa tcaagtctct gtgtgcctgg agagactggg cagtttgacc cttaagcctg
540aagattcaac tgtcctgctc tttgaagctg acacaattac tctgcgccag accatcacca
600catttgggtc tctcaaaacc attcaaattc ctgagcactt gatggctcat gctagttcag
660caaatattgg gcccttcctg gagaagagag gctgtatctc catgccagag cagaagtcag
720catccggtat tgtagctgtc cctttcagcg aatggctcct tggaagcaaa cctgccagtg
780gttatcaagc tccttacata cccagcaccg acccccagga ctggcttacc caaaagcaga
840ccttggagaa cagtcagact tcttccagag cctgcaattt cttcaataat gtcgggggaa
900acctaaaggg cttagaaaac tggctcctca agagtgaaaa atcaagttat caaaagtgta
960acagccattc cactactagt tctttctcca ttgaaatgga aaaggttgga gatcaagagc
1020ttcctgatca agatgagatg gacctatcag attggctagt gactccccag gaatcccata
1080agctgcggaa gcctgagaat ggcagtcgtg aaaccagtga gaagtttaag ctcttattcc
1140agtcctataa tgtgaatgat tggcttgtca agactgactc ctgtaccaac tgtcagggaa
1200accagcccaa aggtgtggag attgaaaacc tgggcaatct gaagtgcctg aatgaccact
1260tggaggccaa gaaaccattg tccaccccca gcatggttac agaggattgg cttgtccaga
1320accatcagga cccatgtaag gtagaggagg tgtgcagagc caatgagccc tgcacaagct
1380ttgcagagtg tgtgtgtgat gagaattgtg agaaggaggc tctgtataag tggcttctga
1440agaaagaagg aaaggataaa aatgggatgc ctgtggaacc caaacctgag cctgagaagc
1500ataaagattc cctgaatatg tggctctgtc ctagaaaaga agtaatagaa caaactaaag
1560caccaaaggc aatgactcct tctagaattg ctgattcctt ccaagtcata aagaacagcc
1620ccttgtcgga gtggcttatc aggcccccat acaaagaagg aagtcccaag gaagtgcctg
1680gtactgaaga cagagctggc aaacagaagt ttaaaagccc catgaatact tcctggtgtt
1740cctttaacac agctgactgg gtcctgccag gaaagaagat gggcaacctc agccagttat
1800cttctggaga agacaagtgg ctgcttcgaa agaaggccca ggaagtatta cttaattcac
1860ctctacagga ggaacataac ttccccccag accattatgg cctccctgca gtttgtgatc
1920tctttgcctg tatgcagctt aaagttgata aagagaagtg gttatatcga actcctctac
1980agatgtgaag gaatggacaa gagttgagca gcctttctgc tgattatcac acatcatgag
2040ctgagtgact gcagcttgcc aaatctttgt gtttctgggt ctgaccaatt agcttagttc
2100ttctcctgcc taattttgaa ctagtaaagc aaagtgagtc atcagattat gagttactgt
2160ttaaaagaaa aatgctgttt attcatgctg aggtgattca gttccctcct tcttacagaa
2220gtattttaat tcaccccaca ctagaaatgc agcatctttg tggacgtctt tttcacaagc
2280ctccaaggct ccttagattg ggtcgttact aaaagtacat taaaacactc ttgtttatcg
2340aagtatattg atgtattcta aagctagtaa acttccctaa cgtttaattg ccctacagat
2400gcttctcttg ctgtgggttt tcttttgtta gtggtctgaa ataattattt tcctgttcta
2460ttaatacata gtgtattttg cacaaaaaaa ttaacctggt caatagtgat taccaaaata
2520tatattaata atcttggcaa tttttgacat taattatgaa acattttagc ccacgttagt
2580tctacattat tcttcactta aactcagcta ctgcaaattt tgtctttctg taaatgttat
2640taaaatatcc agtgagctct ttagaaggac tcagtattat ttcaagacta tttttgaggt
2700aattctagcc ttttaaaata ttctacagac ctacggggct taaaagaacc ccagtaccga
2760ctaagcaaat aggcaaaaga catgttggaa atgtagtata gtacttgaaa cagtcactat
2820catagggata attggtgcat cctgtgtaaa tggaagctga gcttgacacc tggtgctttt
2880aagtagggat aaagtcatcc tctcactgca agcacagcat acctgtacct ccaaaagtga
2940cgttttagtg aacaggccgt tttcaacact tgtgccttgg ggtgttcatt gaagctttgt
3000gaaaactact gatgttttct cagtctcctt aaagttacgt ccatgcttta aaatgtctgt
3060gtaggagaga agtggggttt ataatgtttt ctctaagata tctttgctgc tttccagact
3120ttgaaactat taagcttctt aactgcctct taccggaaat acttctgggg aaacttcatg
3180gtcccaaaat gtcattgcca tacagcttca ctagagttct ttgaaccaca gctgaaaaga
3240gctttgtatt attttttaat tccctcccca gatatcattt aggagtatta tataaaggtg
3300gtgggcaaaa acaatgtaag gagcctttcc agttatcttg agttgcagct ctgtagtttc
3360ttgaggccaa acacactgta ttttacaagt caaaatataa tttacattaa tcactatgtt
3420aatgagtatg taaaacattc ttttgcattg atgaattttg tatctgcttc cattaaaagc
3480ataacagcca taaaaaaaaa aa
350238650PRTHomo sapiensmisc_featureNCOA4 isoform 1 (NP_001138732.1)
38Met Gly Ala Gln Leu Thr Thr Phe Ala Leu Ala Gly Ala Val Arg Arg 1
5 10 15 Met Asn Thr Phe
Gln Asp Gln Ser Gly Ser Ser Ser Asn Arg Glu Pro 20
25 30 Leu Leu Arg Cys Ser Asp Ala Arg Arg
Asp Leu Glu Leu Ala Ile Gly 35 40
45 Gly Val Leu Arg Ala Glu Gln Gln Ile Lys Asp Asn Leu Arg
Glu Val 50 55 60
Lys Ala Gln Ile His Ser Cys Ile Ser Arg His Leu Glu Cys Leu Arg 65
70 75 80 Ser Arg Glu Val Trp
Leu Tyr Glu Gln Val Asp Leu Ile Tyr Gln Leu 85
90 95 Lys Glu Glu Thr Leu Gln Gln Gln Ala Gln
Gln Leu Tyr Ser Leu Leu 100 105
110 Gly Gln Phe Asn Cys Leu Thr His Gln Leu Glu Cys Thr Gln Asn
Lys 115 120 125 Asp
Leu Ala Asn Gln Val Ser Val Cys Leu Glu Arg Leu Gly Ser Leu 130
135 140 Thr Leu Lys Pro Glu
Asp Ser Thr Val Leu Leu Phe Glu Ala Asp Thr 145 150
155 160 Ile Thr Leu Arg Gln Thr Ile Thr Thr Phe
Gly Ser Leu Lys Thr Ile 165 170
175 Gln Ile Pro Glu His Leu Met Ala His Ala Ser Ser Ala Asn Ile
Gly 180 185 190 Pro
Phe Leu Glu Lys Arg Gly Cys Ile Ser Met Pro Glu Gln Lys Ser 195
200 205 Ala Ser Gly Ile Val Ala
Val Pro Phe Ser Glu Trp Leu Leu Gly Ser 210 215
220 Lys Pro Ala Ser Gly Tyr Gln Ala Pro Tyr
Ile Pro Ser Thr Asp Pro 225 230 235
240 Gln Asp Trp Leu Thr Gln Lys Gln Thr Leu Glu Asn Ser Gln Thr
Ser 245 250 255 Ser
Arg Ala Cys Asn Phe Phe Asn Asn Val Gly Gly Asn Leu Lys Gly
260 265 270 Leu Glu Asn Trp Leu
Leu Lys Ser Glu Lys Ser Ser Tyr Gln Lys Cys 275
280 285 Asn Ser His Ser Thr Thr Ser Ser Phe
Ser Ile Glu Met Glu Lys Val 290 295
300 Gly Asp Gln Glu Leu Pro Asp Gln Asp Glu Met Asp Leu
Ser Asp Trp 305 310 315
320 Leu Val Thr Pro Gln Glu Ser His Lys Leu Arg Lys Pro Glu Asn Gly
325 330 335 Ser Arg Glu Thr
Ser Glu Lys Phe Lys Leu Leu Phe Gln Ser Tyr Asn 340
345 350 Val Asn Asp Trp Leu Val Lys Thr Asp
Ser Cys Thr Asn Cys Gln Gly 355 360
365 Asn Gln Pro Lys Gly Val Glu Ile Glu Asn Leu Gly Asn Leu
Lys Cys 370 375 380
Leu Asn Asp His Leu Glu Ala Lys Lys Pro Leu Ser Thr Pro Ser Met 385
390 395 400 Val Thr Glu Asp Trp
Leu Val Gln Asn His Gln Asp Pro Cys Lys Val 405
410 415 Glu Glu Val Cys Arg Ala Asn Glu Pro Cys
Thr Ser Phe Ala Glu Cys 420 425
430 Val Cys Asp Glu Asn Cys Glu Lys Glu Ala Leu Tyr Lys Trp Leu
Leu 435 440 445 Lys
Lys Glu Gly Lys Asp Lys Asn Gly Met Pro Val Glu Pro Lys Pro 450
455 460 Glu Pro Glu Lys His
Lys Asp Ser Leu Asn Met Trp Leu Cys Pro Arg 465 470
475 480 Lys Glu Val Ile Glu Gln Thr Lys Ala Pro
Lys Ala Met Thr Pro Ser 485 490
495 Arg Ile Ala Asp Ser Phe Gln Val Ile Lys Asn Ser Pro Leu Ser
Glu 500 505 510 Trp
Leu Ile Arg Pro Pro Tyr Lys Glu Gly Ser Pro Lys Glu Val Pro 515
520 525 Gly Thr Glu Asp Arg Ala
Gly Lys Gln Lys Phe Lys Ser Pro Met Asn 530 535
540 Thr Ser Trp Cys Ser Phe Asn Thr Ala Asp
Trp Val Leu Pro Gly Lys 545 550 555
560 Lys Met Gly Asn Leu Ser Gln Leu Ser Ser Gly Glu Asp Lys Trp
Leu 565 570 575 Leu
Arg Lys Lys Ala Gln Glu Val Leu Leu Asn Ser Pro Leu Gln Glu
580 585 590 Glu His Asn Phe Pro
Pro Asp His Tyr Gly Leu Pro Ala Val Cys Asp 595
600 605 Leu Phe Ala Cys Met Gln Leu Lys Val
Asp Lys Glu Lys Trp Leu Tyr 610 615
620 Arg Thr Pro Leu Gln Ala Tyr Phe Lys Met Asn Phe Gln
Asp Val Thr 625 630 635
640 Val Gly Asn Phe Gln Ile Pro Cys Gly Phe 645
650 39630PRTHomo sapiensmisc_featureNCOA4 isoform 2
(NP_001138733.1) 39Met Gly Ala Gln Leu Thr Thr Phe Ala Leu Ala Gly Ala
Val Arg Arg 1 5 10 15
Met Asn Thr Phe Gln Asp Gln Ser Gly Ser Ser Ser Asn Arg Glu Pro
20 25 30 Leu Leu Arg Cys
Ser Asp Ala Arg Arg Asp Leu Glu Leu Ala Ile Gly 35
40 45 Gly Val Leu Arg Ala Glu Gln Gln
Ile Lys Asp Asn Leu Arg Glu Val 50 55
60 Lys Ala Gln Ile His Ser Cys Ile Ser Arg His Leu Glu
Cys Leu Arg 65 70 75
80 Ser Arg Glu Val Trp Leu Tyr Glu Gln Val Asp Leu Ile Tyr Gln Leu
85 90 95 Lys Glu Glu Thr
Leu Gln Gln Gln Ala Gln Gln Leu Tyr Ser Leu Leu 100
105 110 Gly Gln Phe Asn Cys Leu Thr His Gln
Leu Glu Cys Thr Gln Asn Lys 115 120
125 Asp Leu Ala Asn Gln Val Ser Val Cys Leu Glu Arg Leu Gly
Ser Leu 130 135 140
Thr Leu Lys Pro Glu Asp Ser Thr Val Leu Leu Phe Glu Ala Asp Thr 145
150 155 160 Ile Thr Leu Arg Gln
Thr Ile Thr Thr Phe Gly Ser Leu Lys Thr Ile 165
170 175 Gln Ile Pro Glu His Leu Met Ala His Ala
Ser Ser Ala Asn Ile Gly 180 185
190 Pro Phe Leu Glu Lys Arg Gly Cys Ile Ser Met Pro Glu Gln Lys
Ser 195 200 205 Ala
Ser Gly Ile Val Ala Val Pro Phe Ser Glu Trp Leu Leu Gly Ser 210
215 220 Lys Pro Ala Ser Gly
Tyr Gln Ala Pro Tyr Ile Pro Ser Thr Asp Pro 225 230
235 240 Gln Asp Trp Leu Thr Gln Lys Gln Thr Leu
Glu Asn Ser Gln Thr Ser 245 250
255 Ser Arg Ala Cys Asn Phe Phe Asn Asn Val Gly Gly Asn Leu Lys
Gly 260 265 270 Leu
Glu Asn Trp Leu Leu Lys Ser Glu Lys Ser Ser Tyr Gln Lys Cys 275
280 285 Asn Ser His Ser Thr Thr
Ser Ser Phe Ser Ile Glu Met Glu Lys Val 290 295
300 Gly Asp Gln Glu Leu Pro Asp Gln Asp Glu
Met Asp Leu Ser Asp Trp 305 310 315
320 Leu Val Thr Pro Gln Glu Ser His Lys Leu Arg Lys Pro Glu Asn
Gly 325 330 335 Ser
Arg Glu Thr Ser Glu Lys Phe Lys Leu Leu Phe Gln Ser Tyr Asn
340 345 350 Val Asn Asp Trp Leu
Val Lys Thr Asp Ser Cys Thr Asn Cys Gln Gly 355
360 365 Asn Gln Pro Lys Gly Val Glu Ile Glu
Asn Leu Gly Asn Leu Lys Cys 370 375
380 Leu Asn Asp His Leu Glu Ala Lys Lys Pro Leu Ser Thr
Pro Ser Met 385 390 395
400 Val Thr Glu Asp Trp Leu Val Gln Asn His Gln Asp Pro Cys Lys Val
405 410 415 Glu Glu Val Cys
Arg Ala Asn Glu Pro Cys Thr Ser Phe Ala Glu Cys 420
425 430 Val Cys Asp Glu Asn Cys Glu Lys Glu
Ala Leu Tyr Lys Trp Leu Leu 435 440
445 Lys Lys Glu Gly Lys Asp Lys Asn Gly Met Pro Val Glu Pro
Lys Pro 450 455 460
Glu Pro Glu Lys His Lys Asp Ser Leu Asn Met Trp Leu Cys Pro Arg 465
470 475 480 Lys Glu Val Ile Glu
Gln Thr Lys Ala Pro Lys Ala Met Thr Pro Ser 485
490 495 Arg Ile Ala Asp Ser Phe Gln Val Ile Lys
Asn Ser Pro Leu Ser Glu 500 505
510 Trp Leu Ile Arg Pro Pro Tyr Lys Glu Gly Ser Pro Lys Glu Val
Pro 515 520 525 Gly
Thr Glu Asp Arg Ala Gly Lys Gln Lys Phe Lys Ser Pro Met Asn 530
535 540 Thr Ser Trp Cys Ser
Phe Asn Thr Ala Asp Trp Val Leu Pro Gly Lys 545 550
555 560 Lys Met Gly Asn Leu Ser Gln Leu Ser Ser
Gly Glu Asp Lys Trp Leu 565 570
575 Leu Arg Lys Lys Ala Gln Glu Val Leu Leu Asn Ser Pro Leu Gln
Glu 580 585 590 Glu
His Asn Phe Pro Pro Asp His Tyr Gly Leu Pro Ala Val Cys Asp 595
600 605 Leu Phe Ala Cys Met Gln
Leu Lys Val Asp Lys Glu Lys Trp Leu Tyr 610 615
620 Arg Thr Pro Leu Gln Met 625
630 40614PRTHomo sapiensmisc_featureNCOA4 isoform 3 (NP_001138734.1)
40Met Asn Thr Phe Gln Asp Gln Ser Gly Ser Ser Ser Asn Arg Glu Pro 1
5 10 15 Leu Leu Arg Cys
Ser Asp Ala Arg Arg Asp Leu Glu Leu Ala Ile Gly 20
25 30 Gly Val Leu Arg Ala Glu Gln Gln Ile
Lys Asp Asn Leu Arg Glu Val 35 40
45 Lys Ala Gln Ile His Ser Cys Ile Ser Arg His Leu Glu Cys
Leu Arg 50 55 60
Ser Arg Glu Val Trp Leu Tyr Glu Gln Val Asp Leu Ile Tyr Gln Leu 65
70 75 80 Lys Glu Glu Thr Leu
Gln Gln Gln Ala Gln Gln Leu Tyr Ser Leu Leu 85
90 95 Gly Gln Phe Asn Cys Leu Thr His Gln Leu
Glu Cys Thr Gln Asn Lys 100 105
110 Asp Leu Ala Asn Gln Val Ser Val Cys Leu Glu Arg Leu Gly Ser
Leu 115 120 125 Thr
Leu Lys Pro Glu Asp Ser Thr Val Leu Leu Phe Glu Ala Asp Thr 130
135 140 Ile Thr Leu Arg Gln
Thr Ile Thr Thr Phe Gly Ser Leu Lys Thr Ile 145 150
155 160 Gln Ile Pro Glu His Leu Met Ala His Ala
Ser Ser Ala Asn Ile Gly 165 170
175 Pro Phe Leu Glu Lys Arg Gly Cys Ile Ser Met Pro Glu Gln Lys
Ser 180 185 190 Ala
Ser Gly Ile Val Ala Val Pro Phe Ser Glu Trp Leu Leu Gly Ser 195
200 205 Lys Pro Ala Ser Gly Tyr
Gln Ala Pro Tyr Ile Pro Ser Thr Asp Pro 210 215
220 Gln Asp Trp Leu Thr Gln Lys Gln Thr Leu
Glu Asn Ser Gln Thr Ser 225 230 235
240 Ser Arg Ala Cys Asn Phe Phe Asn Asn Val Gly Gly Asn Leu Lys
Gly 245 250 255 Leu
Glu Asn Trp Leu Leu Lys Ser Glu Lys Ser Ser Tyr Gln Lys Cys
260 265 270 Asn Ser His Ser Thr
Thr Ser Ser Phe Ser Ile Glu Met Glu Lys Val 275
280 285 Gly Asp Gln Glu Leu Pro Asp Gln Asp
Glu Met Asp Leu Ser Asp Trp 290 295
300 Leu Val Thr Pro Gln Glu Ser His Lys Leu Arg Lys Pro
Glu Asn Gly 305 310 315
320 Ser Arg Glu Thr Ser Glu Lys Phe Lys Leu Leu Phe Gln Ser Tyr Asn
325 330 335 Val Asn Asp Trp
Leu Val Lys Thr Asp Ser Cys Thr Asn Cys Gln Gly 340
345 350 Asn Gln Pro Lys Gly Val Glu Ile Glu
Asn Leu Gly Asn Leu Lys Cys 355 360
365 Leu Asn Asp His Leu Glu Ala Lys Lys Pro Leu Ser Thr Pro
Ser Met 370 375 380
Val Thr Glu Asp Trp Leu Val Gln Asn His Gln Asp Pro Cys Lys Val 385
390 395 400 Glu Glu Val Cys Arg
Ala Asn Glu Pro Cys Thr Ser Phe Ala Glu Cys 405
410 415 Val Cys Asp Glu Asn Cys Glu Lys Glu Ala
Leu Tyr Lys Trp Leu Leu 420 425
430 Lys Lys Glu Gly Lys Asp Lys Asn Gly Met Pro Val Glu Pro Lys
Pro 435 440 445 Glu
Pro Glu Lys His Lys Asp Ser Leu Asn Met Trp Leu Cys Pro Arg 450
455 460 Lys Glu Val Ile Glu
Gln Thr Lys Ala Pro Lys Ala Met Thr Pro Ser 465 470
475 480 Arg Ile Ala Asp Ser Phe Gln Val Ile Lys
Asn Ser Pro Leu Ser Glu 485 490
495 Trp Leu Ile Arg Pro Pro Tyr Lys Glu Gly Ser Pro Lys Glu Val
Pro 500 505 510 Gly
Thr Glu Asp Arg Ala Gly Lys Gln Lys Phe Lys Ser Pro Met Asn 515
520 525 Thr Ser Trp Cys Ser Phe
Asn Thr Ala Asp Trp Val Leu Pro Gly Lys 530 535
540 Lys Met Gly Asn Leu Ser Gln Leu Ser Ser
Gly Glu Asp Lys Trp Leu 545 550 555
560 Leu Arg Lys Lys Ala Gln Glu Val Leu Leu Asn Ser Pro Leu Gln
Glu 565 570 575 Glu
His Asn Phe Pro Pro Asp His Tyr Gly Leu Pro Ala Val Cys Asp
580 585 590 Leu Phe Ala Cys Met
Gln Leu Lys Val Asp Lys Glu Lys Trp Leu Tyr 595
600 605 Arg Thr Pro Leu Gln Met 610
41614PRTHomo sapiensmisc_featureNCOA4 isoform 3
(NP_001138735.1) 41Met Asn Thr Phe Gln Asp Gln Ser Gly Ser Ser Ser Asn
Arg Glu Pro 1 5 10 15
Leu Leu Arg Cys Ser Asp Ala Arg Arg Asp Leu Glu Leu Ala Ile Gly
20 25 30 Gly Val Leu Arg
Ala Glu Gln Gln Ile Lys Asp Asn Leu Arg Glu Val 35
40 45 Lys Ala Gln Ile His Ser Cys Ile Ser
Arg His Leu Glu Cys Leu Arg 50 55
60 Ser Arg Glu Val Trp Leu Tyr Glu Gln Val Asp Leu Ile
Tyr Gln Leu 65 70 75
80 Lys Glu Glu Thr Leu Gln Gln Gln Ala Gln Gln Leu Tyr Ser Leu Leu
85 90 95 Gly Gln Phe Asn
Cys Leu Thr His Gln Leu Glu Cys Thr Gln Asn Lys 100
105 110 Asp Leu Ala Asn Gln Val Ser Val Cys
Leu Glu Arg Leu Gly Ser Leu 115 120
125 Thr Leu Lys Pro Glu Asp Ser Thr Val Leu Leu Phe Glu Ala
Asp Thr 130 135 140
Ile Thr Leu Arg Gln Thr Ile Thr Thr Phe Gly Ser Leu Lys Thr Ile 145
150 155 160 Gln Ile Pro Glu His
Leu Met Ala His Ala Ser Ser Ala Asn Ile Gly 165
170 175 Pro Phe Leu Glu Lys Arg Gly Cys Ile Ser
Met Pro Glu Gln Lys Ser 180 185
190 Ala Ser Gly Ile Val Ala Val Pro Phe Ser Glu Trp Leu Leu Gly
Ser 195 200 205 Lys
Pro Ala Ser Gly Tyr Gln Ala Pro Tyr Ile Pro Ser Thr Asp Pro 210
215 220 Gln Asp Trp Leu Thr
Gln Lys Gln Thr Leu Glu Asn Ser Gln Thr Ser 225 230
235 240 Ser Arg Ala Cys Asn Phe Phe Asn Asn Val
Gly Gly Asn Leu Lys Gly 245 250
255 Leu Glu Asn Trp Leu Leu Lys Ser Glu Lys Ser Ser Tyr Gln Lys
Cys 260 265 270 Asn
Ser His Ser Thr Thr Ser Ser Phe Ser Ile Glu Met Glu Lys Val 275
280 285 Gly Asp Gln Glu Leu Pro
Asp Gln Asp Glu Met Asp Leu Ser Asp Trp 290 295
300 Leu Val Thr Pro Gln Glu Ser His Lys Leu
Arg Lys Pro Glu Asn Gly 305 310 315
320 Ser Arg Glu Thr Ser Glu Lys Phe Lys Leu Leu Phe Gln Ser Tyr
Asn 325 330 335 Val
Asn Asp Trp Leu Val Lys Thr Asp Ser Cys Thr Asn Cys Gln Gly
340 345 350 Asn Gln Pro Lys Gly
Val Glu Ile Glu Asn Leu Gly Asn Leu Lys Cys 355
360 365 Leu Asn Asp His Leu Glu Ala Lys Lys
Pro Leu Ser Thr Pro Ser Met 370 375
380 Val Thr Glu Asp Trp Leu Val Gln Asn His Gln Asp Pro
Cys Lys Val 385 390 395
400 Glu Glu Val Cys Arg Ala Asn Glu Pro Cys Thr Ser Phe Ala Glu Cys
405 410 415 Val Cys Asp Glu
Asn Cys Glu Lys Glu Ala Leu Tyr Lys Trp Leu Leu 420
425 430 Lys Lys Glu Gly Lys Asp Lys Asn Gly
Met Pro Val Glu Pro Lys Pro 435 440
445 Glu Pro Glu Lys His Lys Asp Ser Leu Asn Met Trp Leu Cys
Pro Arg 450 455 460
Lys Glu Val Ile Glu Gln Thr Lys Ala Pro Lys Ala Met Thr Pro Ser 465
470 475 480 Arg Ile Ala Asp Ser
Phe Gln Val Ile Lys Asn Ser Pro Leu Ser Glu 485
490 495 Trp Leu Ile Arg Pro Pro Tyr Lys Glu Gly
Ser Pro Lys Glu Val Pro 500 505
510 Gly Thr Glu Asp Arg Ala Gly Lys Gln Lys Phe Lys Ser Pro Met
Asn 515 520 525 Thr
Ser Trp Cys Ser Phe Asn Thr Ala Asp Trp Val Leu Pro Gly Lys 530
535 540 Lys Met Gly Asn Leu
Ser Gln Leu Ser Ser Gly Glu Asp Lys Trp Leu 545 550
555 560 Leu Arg Lys Lys Ala Gln Glu Val Leu Leu
Asn Ser Pro Leu Gln Glu 565 570
575 Glu His Asn Phe Pro Pro Asp His Tyr Gly Leu Pro Ala Val Cys
Asp 580 585 590 Leu
Phe Ala Cys Met Gln Leu Lys Val Asp Lys Glu Lys Trp Leu Tyr 595
600 605 Arg Thr Pro Leu Gln Met
610 42614PRTHomo sapiensmisc_featureNCOA4 isoform 3
(NP_005428.1) 42Met Asn Thr Phe Gln Asp Gln Ser Gly Ser Ser Ser Asn Arg
Glu Pro 1 5 10 15
Leu Leu Arg Cys Ser Asp Ala Arg Arg Asp Leu Glu Leu Ala Ile Gly
20 25 30 Gly Val Leu Arg Ala
Glu Gln Gln Ile Lys Asp Asn Leu Arg Glu Val 35
40 45 Lys Ala Gln Ile His Ser Cys Ile Ser
Arg His Leu Glu Cys Leu Arg 50 55
60 Ser Arg Glu Val Trp Leu Tyr Glu Gln Val Asp Leu Ile
Tyr Gln Leu 65 70 75
80 Lys Glu Glu Thr Leu Gln Gln Gln Ala Gln Gln Leu Tyr Ser Leu Leu
85 90 95 Gly Gln Phe Asn
Cys Leu Thr His Gln Leu Glu Cys Thr Gln Asn Lys 100
105 110 Asp Leu Ala Asn Gln Val Ser Val Cys
Leu Glu Arg Leu Gly Ser Leu 115 120
125 Thr Leu Lys Pro Glu Asp Ser Thr Val Leu Leu Phe Glu Ala
Asp Thr 130 135 140
Ile Thr Leu Arg Gln Thr Ile Thr Thr Phe Gly Ser Leu Lys Thr Ile 145
150 155 160 Gln Ile Pro Glu His
Leu Met Ala His Ala Ser Ser Ala Asn Ile Gly 165
170 175 Pro Phe Leu Glu Lys Arg Gly Cys Ile Ser
Met Pro Glu Gln Lys Ser 180 185
190 Ala Ser Gly Ile Val Ala Val Pro Phe Ser Glu Trp Leu Leu Gly
Ser 195 200 205 Lys
Pro Ala Ser Gly Tyr Gln Ala Pro Tyr Ile Pro Ser Thr Asp Pro 210
215 220 Gln Asp Trp Leu Thr
Gln Lys Gln Thr Leu Glu Asn Ser Gln Thr Ser 225 230
235 240 Ser Arg Ala Cys Asn Phe Phe Asn Asn Val
Gly Gly Asn Leu Lys Gly 245 250
255 Leu Glu Asn Trp Leu Leu Lys Ser Glu Lys Ser Ser Tyr Gln Lys
Cys 260 265 270 Asn
Ser His Ser Thr Thr Ser Ser Phe Ser Ile Glu Met Glu Lys Val 275
280 285 Gly Asp Gln Glu Leu Pro
Asp Gln Asp Glu Met Asp Leu Ser Asp Trp 290 295
300 Leu Val Thr Pro Gln Glu Ser His Lys Leu
Arg Lys Pro Glu Asn Gly 305 310 315
320 Ser Arg Glu Thr Ser Glu Lys Phe Lys Leu Leu Phe Gln Ser Tyr
Asn 325 330 335 Val
Asn Asp Trp Leu Val Lys Thr Asp Ser Cys Thr Asn Cys Gln Gly
340 345 350 Asn Gln Pro Lys Gly
Val Glu Ile Glu Asn Leu Gly Asn Leu Lys Cys 355
360 365 Leu Asn Asp His Leu Glu Ala Lys Lys
Pro Leu Ser Thr Pro Ser Met 370 375
380 Val Thr Glu Asp Trp Leu Val Gln Asn His Gln Asp Pro
Cys Lys Val 385 390 395
400 Glu Glu Val Cys Arg Ala Asn Glu Pro Cys Thr Ser Phe Ala Glu Cys
405 410 415 Val Cys Asp Glu
Asn Cys Glu Lys Glu Ala Leu Tyr Lys Trp Leu Leu 420
425 430 Lys Lys Glu Gly Lys Asp Lys Asn Gly
Met Pro Val Glu Pro Lys Pro 435 440
445 Glu Pro Glu Lys His Lys Asp Ser Leu Asn Met Trp Leu Cys
Pro Arg 450 455 460
Lys Glu Val Ile Glu Gln Thr Lys Ala Pro Lys Ala Met Thr Pro Ser 465
470 475 480 Arg Ile Ala Asp Ser
Phe Gln Val Ile Lys Asn Ser Pro Leu Ser Glu 485
490 495 Trp Leu Ile Arg Pro Pro Tyr Lys Glu Gly
Ser Pro Lys Glu Val Pro 500 505
510 Gly Thr Glu Asp Arg Ala Gly Lys Gln Lys Phe Lys Ser Pro Met
Asn 515 520 525 Thr
Ser Trp Cys Ser Phe Asn Thr Ala Asp Trp Val Leu Pro Gly Lys 530
535 540 Lys Met Gly Asn Leu
Ser Gln Leu Ser Ser Gly Glu Asp Lys Trp Leu 545 550
555 560 Leu Arg Lys Lys Ala Gln Glu Val Leu Leu
Asn Ser Pro Leu Gln Glu 565 570
575 Glu His Asn Phe Pro Pro Asp His Tyr Gly Leu Pro Ala Val Cys
Asp 580 585 590 Leu
Phe Ala Cys Met Gln Leu Lys Val Asp Lys Glu Lys Trp Leu Tyr 595
600 605 Arg Thr Pro Leu Gln Met
610 438339DNAHomo sapiensmisc_featureTRIM33
transcript variant a (NM_015906.3) 43ctgcggctgg ggctgggggc ggcggcggcg
gcgacgcggg cggcgggcgg cgcggggcgg 60tccggcgggt tcaaagagga aaacatggcg
gaaaacaaag gcggcggcga ggctgagagc 120ggcggcgggg gcagcggcag cgcgccggta
actgccgggg ccgccgggcc cgccgcgcag 180gaggcggagc cgcctctcac cgcggtgctg
gtggaggagg aggaggagga aggcggcagg 240gccggcgctg agggcggcgc ggccgggccc
gacgacgggg gggtggccgc ggcctcctcg 300ggctcggccc aggctgcttc atctcctgcg
gcctcagtgg gcactggagt tgccgggggc 360gcagtatcga cgccggctcc agctccagcc
tcggctcccg ctccgggtcc ctcggcaggg 420ccgcctcctg gaccgccagc ctcgctcctg
gacacctgcg ccgtgtgtca gcagagcttg 480cagagccggc gtgaggcgga gcccaagctg
ctgccctgtc ttcactcctt ctgcctgcgc 540tgcctgcccg agccggagcg ccagctcagc
gtgcccatcc cggggggcag caacggcgac 600atccagcaag ttggtgtaat acggtgccca
gtatgccgcc aagaatgcag acagatagac 660cttgtggata attattttgt gaaagacaca
tctgaagctc ctagcagttc tgatgaaaaa 720tcagaacagg tatgtactag ttgtgaagac
aatgcaagtg cagttggctt ttgtgtagaa 780tgtggagagt ggctatgtaa gacatgtatc
gaagcacatc aaagagtaaa atttactaaa 840gatcacttga tcaggaagaa agaagatgtc
tcagagtctg ttggagcatc tggtcaacgc 900cctgttttct gccctgtaca caaacaagaa
cagttgaaac ttttctgtga aacatgtgat 960agattgacat gtagagactg tcagctattg
gaacacaaag aacataggta tcagtttttg 1020gaagaagctt ttcaaaatca gaagggtgca
attgagaatc tactggcgaa acttcttgag 1080aagaagaatt atgttcattt tgcagctact
caggtgcaga ataggataaa agaagtaaat 1140gagactaaca aacgagtaga acaggaaatt
aaagtggcca ttttcaccct tatcaatgaa 1200attaataaga aaggaaaatc tctcttacaa
cagctagaga atgttacaaa ggaaagacag 1260atgaagttac tacagcagca gaatgacatc
acaggccttt cccggcaggt gaagcatgtt 1320atgaacttca caaattgggc aattgcaagt
ggcagcagca cagcactact atacagcaag 1380cgactgatta ctttccagtt gcgtcatatt
ttgaaagcac ggtgtgatcc tgtccctgct 1440gctaatggag caatacgttt ccattgtgat
cccaccttct gggcaaagaa tgtagtcaat 1500ttaggtaatc tagtaataga gagtaaacca
gctcctggtt atactcctaa tgttgtagtt 1560gggcaagttc ctccagggac aaaccacatt
agtaaaaccc ctggacagat taacttagca 1620cagcttcgac tccagcacat gcaacaacaa
gtatatgcac agaaacatca gcagttgcaa 1680cagatgagga tgcagcaacc accagcacct
gtaccaacta caacaacaac aacacaacag 1740catcctagac aagcagcccc tcagatgtta
caacaacagc ctcctcgatt gatcagtgtg 1800caaacaatgc aaagaggcaa catgaactgt
ggagcttttc aagcccatca gatgagactg 1860gctcagaatg ctgccagaat accagggata
cccaggcaca gcggccctca atattccatg 1920atgcagccac acctccaaag acaacactca
aacccagggc atgctggacc ctttcccgta 1980gtatcggtac acaacaccac aatcaaccca
acgagcccta ctacagcaac tatggcaaat 2040gcaaaccgag gtcccaccag cccatctgtt
acagcaatag agctaatccc ctcagttacc 2100aatccagaaa accttccatc gctgccagat
attccaccca tacagttgga agatgctggc 2160tcaagtagtt tagataatct actaagtaga
tacatctcag gcagtcacct acccccacag 2220cctacaagca ccatgaatcc ttctccaggt
ccctctgccc tttctccggg atcatcaggt 2280ttatccaatt ctcacacacc tgtgagaccc
ccaagtactt ctagtactgg cagtcgaggc 2340agctgtgggt catcaggaag aactgctgag
aagacaagtc ttagtttcaa atctgatcag 2400gtgaaggtca agcaagaacc tgggactgaa
gatgaaatat gtagcttttc aggaggtgta 2460aaacaagaaa aaacagagga tggcaggagg
agtgcttgca tgttgagcag tcctgagagt 2520agcttgacac cacctctctc aaccaacctg
catctagaaa gtgaattgga tgcattggca 2580agcctggaaa accatgtgaa aattgaacct
gcagatatga atgaaagctg caaacagtca 2640gggctcagca gccttgttaa tggaaagtcc
ccaattcgaa gcctcatgca caggtcggca 2700aggattggag gagatggcaa caataaagat
gatgacccaa atgaagactg gtgtgctgtc 2760tgccaaaacg gaggagatct cttgtgctgc
gaaaaatgtc caaaggtctt tcatctaact 2820tgtcatgttc caacactact tagctttcca
agtggggact ggatatgcac attttgtaga 2880gatattggaa agccagaagt tgaatatgat
tgtgataatt tgcaacatag taagaagggg 2940aaaactgcgc aggggttaag ccccgtggac
caaaggaaat gtgaacgtct tctgctttac 3000ctctattgcc atgaattaag tattgaattc
caggagcctg ttcctgcttc gataccaaac 3060tactataaaa ttataaagaa accaatggat
ttatccaccg tgaaaaagaa gcttcagaaa 3120aaacattccc aacactacca aatcccggat
gactttgtgg ccgatgtccg tttgatcttc 3180aagaactgtg aaaggtttaa tgaaatgatg
aaagttgttc aagtttatgc agacacacaa 3240gagattaatt tgaaggctga ttcagaagta
gctcaggcag ggaaagcagt tgcattgtac 3300tttgaagata aactcacaga gatctactca
gacaggacct tcgcaccttt gccagagttt 3360gagcaggaag aggatgatgg tgaggtaact
gaggactctg atgaagactt tatacagccc 3420cgcagaaaac gcctaaagtc agatgagaga
ccagtacata taaagtaaaa tgacatggat 3480ttaaatcaat tgtttaaaaa aaaaaaaacg
aaaaaaaaaa aaaaaacaca aaaaacccag 3540aaaactttta agtgttgctg gaatatcctg
cctacagtgg gcacctcctt gaagaagctg 3600atagctttta cacagtatta gattgaaata
atggacagaa acacattctt gtcaagaaag 3660ggggagagaa gtctgtttgc aagtttcaaa
gcaaaaagca aaagtgaaat gatttgagga 3720tttctgttct aatggagatg attctctgat
tgttagaaat ggcaaatatt gatgattgtg 3780tgctattgat tggtgcagga tacttggtat
acgagtaaat acttgagact cgtgtcactt 3840gataaatttt ctttttggac taggtcgcac
agttattaaa acaactttta accctccccc 3900ttcacacaca tacatatcag gttgttttct
agttaaaaac ccaagtagct cagattctac 3960tttaatgtca gtgcagattt gcattgaatc
atgccattat gttttttctc atttttatgc 4020tgttgggtct tagtttttaa attgatataa
agaactcagc aatggtttta ttttctactc 4080atacttaggg tttaggaaac actaccacta
gttatcattt aatcaacttc aatggtctac 4140tgaaacaaaa atggtaactt ttcattagtg
gattatttag agttatagta gttgtttcca 4200gaaaacactt cctcacaatt gtacttccca
atcaaatcat gtgatcatac agttattccc 4260atgaaaggca gaatgtttgt ttcaaaatta
atctagtttt ctgtacattt aaatttgaga 4320aggtgacaac tggctctttt ccagtcttcc
ttcatgtcag ttttctgata gaccactatt 4380ggcaaacagt atctgtcaac taccaaatgt
gtaaaatttt ctgtatttca ctttgtctta 4440tttgtaaata gtgaactaaa acttttggca
gatcagcaac atttgctgag cctgtttttt 4500aagctaatgt gtattcttac taatgttcct
atcaagaatg gatttgtaat atatgctgtc 4560tatttctaat gttcacattc atattttgag
gttctatctt attttaatag agaacagact 4620tctcaaaaaa tcttcagaag cagcttatta
ttgaaatatc gaaatattga aataaacccg 4680gtggggttag attactcatc tgtccaccaa
gtgggacatt tgcatggact gggggcttaa 4740aggacttaga agagacctgt aagtaaatcc
tgaaaatgag ccaatcccca cttgaatggt 4800tactggagta aacccacctt taccacccca
attacagcac ccgaggccga taaaccaact 4860tggctctggt tcatttttct tttcttcatt
tgtgatgctc agattcaaaa tgtgtgttct 4920acactgttac aggcttctct tttgtttgat
taaagatttt agtcctactt ttgtatggac 4980acattagaat attcagagac caaaatagaa
gaatttgctg ttagatattt ttcagaagtc 5040agcagatttg tggcaaatca tttatttgcc
tttttaaaaa ttcatttaag cagttcagag 5100agtagactac tcagaaaatt atttcacgta
attgtctaag aggtcaatat tttttaatgc 5160atattgaatc aaataaagtg ctctaaagaa
attattatac aaattccttt gggttgtttt 5220tcttttctta acaaggggtg ggggtaaaca
ggaatatgat tcaggctttc tggttgtgta 5280tttaaagagt attgatttta ttattactat
tgatttactt tattcctggc ttccttttca 5340cttttctttc aatttttaaa aaataattta
agccgttgaa aatataccaa actgttgaaa 5400cattttactc aaattttaaa ttcctaaaaa
tgttttttaa taagagggag aaaattattt 5460aaaaatactt atgcctatgc caatttccct
cttttttcac aaaatccatg atttcagttt 5520gtaagtagac atatatctaa gggcacattt
ttggaaagtg aggaatagca gcagtataac 5580ttcattttgt caggcctttg agttctaata
ttttgtattg ctcttcaaat ggatcctttt 5640aaaaaaattg tagataatga gtcataaata
gattctgcca actgagggga gaaacatttt 5700aagtaaatat ttttcagtat ttggggcctt
aaaaaataat tgtgtttcct taaaattaca 5760tgttagatag agtttttagg tttttttggt
tttaagattg gttaaagcaa tttaaaagcc 5820acttttttgt caacatttaa tagcctccac
ttctgttaag ataatgtata ctgctgagga 5880attactatta atagctatca acataccacc
attaaattaa ggtattcact ttagattttt 5940tattaaagct tttttcttgc acactgatcg
ttgtgtttct aagctgattt tttcagctct 6000aatataccta tggttaaaaa gtataaaaac
ttaaattgat atttagatat atgttttcct 6060attagtttat gttttaaaaa gacaaaattg
tatctgtcag tccctgaagg cagtttgttt 6120ttatactctc tcacatttgt atttgttttt
taaatggcag tattttagaa gatttggaga 6180aaagtccaca taataatgtt ttcttaaaag
cttttaaagt ttttgctgta cttcaattta 6240cttcttccat cagaaaacta agaacaaagt
gttgctcagt ctgttccgct gacctaaatt 6300tgtgttttca gcacttggct cagccaattc
actgagtgaa ggaattgctt tatgaggcaa 6360agcatgtgaa agttctaaag tatggttaga
ttgtaggtcg tgctctatat ggaaacatca 6420aaccattact acagagaaat gataaggcat
tggatccact attgaaatta ttatttttgg 6480atcaacaagt tggtactttc tgacttctgt
atcttaacat aagggaattt taggtaatgc 6540taagtcagtt gtctcatttt ttgtgataag
ttttggaatt tttagttaat tgaaataaat 6600aatgctttta aatagaagta aaaggtttat
aagtgtgcaa attgtagatt tatcaattac 6660ctcagcaggt atcctgccat gtaattatta
gtgattagtg ttaataagat aatagattca 6720ggtcttccaa ctatgccctt ggattgtggc
ctactgtatg ttattaaatg gtctcttact 6780atccaaaatg ggagtagatg ctgtggcccc
gtctcccttg gcttttacgt cccatatcca 6840cccccattca tgtacaacat gtgaaatata
aaaatctcat ttcttgtcaa aatcagcact 6900gcttatttgc atactcagca tcggatcagt
gagtagtttt ataaaaaatc cacgcaccca 6960actcccttag ttaaaacaga ttcttaattc
ataccatgaa ttcttaattt ctgtaccatc 7020tatgttaatg atctgctgaa ggtgactcaa
gattttcaag gtgtaataca gtttgatcat 7080gtaccggacc tggatattta attttttttc
cctcacagtt aatctcctcc ttgataaagc 7140aataacactg ctttgagtct gttgcctaat
agcatgtcag aatcctctcc tggatggtga 7200ttttatagga aagtttgtat gcatatcacc
cagtctatct tttaaaaatt aagaaattta 7260aatgtatgct ggaagtaatg acactatatt
gtggcatttt attttaaaaa ttggggaaag 7320ttgcatattt ttttaaaagt aagtgtttga
gtaaaaaaat tgaaggtact tttttaagga 7380aaaaaattta tatgccacag tttacataga
catttcagat tcaacacgta ctcttgaata 7440taatggtttc ttttacttgg tcaaaatgca
tgtatagcat ttctttcatc ttagttcctt 7500gtgtttgcct atgtggtcct ttatatattt
tttattgtat cgaagaaaca aaactatctt 7560caaaaataag ttaatttgga tatatttgtc
atatcaaact acaaagtgta caaagttaag 7620tttagccctt ttctagaaag tgatctttaa
aattaaaaat gctcctcttt taaattcacc 7680aaatttatgt gtgggaaggc accaaaatga
ttttgtaagt gccactgcaa tattcccttt 7740caagtgtggc ctaaatttca atcttaagga
tggaatgcat gtctgctcct tgttctgaaa 7800aatgtaggca tctactacat tttaaaacac
agtgaaacat atacataagc ctataaaaaa 7860agatttgtgc aatttgaaag cctgttaatt
ttttatgtag acatacctac acacgaaagg 7920gttaaattca cagccttact agttccttgc
ttccagtatt tcaattggtc tcctcccctc 7980attattatta ttactactag tactattatt
tttgcacata gttaactgcc cttcaatatg 8040attcttaaaa agtgctgttt ctgtggtatc
gtattctcta aataatcata tttaattttt 8100taaaacaagg ttgcagtttc taattgtttc
gttcctgtgt ttttgctggt gtgtaataaa 8160agcaagtttt ttcttttcat ggttatttaa
tacattagct gcctgtaaat aattcttgtt 8220ataatgctct ggaatgtgtt gtagaagttg
tattagatta gttttaaacc cttgtttgaa 8280agccacattg ttttggttat ttctattaaa
ttagaaaatt gaaaaagttt tcaaatgaa 8339448288DNAHomo
sapiensmisc_featureTRIM33 transcript variant b (NM_033020.2) 44ctgcggctgg
ggctgggggc ggcggcggcg gcgacgcggg cggcgggcgg cgcggggcgg 60tccggcgggt
tcaaagagga aaacatggcg gaaaacaaag gcggcggcga ggctgagagc 120ggcggcgggg
gcagcggcag cgcgccggta actgccgggg ccgccgggcc cgccgcgcag 180gaggcggagc
cgcctctcac cgcggtgctg gtggaggagg aggaggagga aggcggcagg 240gccggcgctg
agggcggcgc ggccgggccc gacgacgggg gggtggccgc ggcctcctcg 300ggctcggccc
aggctgcttc atctcctgcg gcctcagtgg gcactggagt tgccgggggc 360gcagtatcga
cgccggctcc agctccagcc tcggctcccg ctccgggtcc ctcggcaggg 420ccgcctcctg
gaccgccagc ctcgctcctg gacacctgcg ccgtgtgtca gcagagcttg 480cagagccggc
gtgaggcgga gcccaagctg ctgccctgtc ttcactcctt ctgcctgcgc 540tgcctgcccg
agccggagcg ccagctcagc gtgcccatcc cggggggcag caacggcgac 600atccagcaag
ttggtgtaat acggtgccca gtatgccgcc aagaatgcag acagatagac 660cttgtggata
attattttgt gaaagacaca tctgaagctc ctagcagttc tgatgaaaaa 720tcagaacagg
tatgtactag ttgtgaagac aatgcaagtg cagttggctt ttgtgtagaa 780tgtggagagt
ggctatgtaa gacatgtatc gaagcacatc aaagagtaaa atttactaaa 840gatcacttga
tcaggaagaa agaagatgtc tcagagtctg ttggagcatc tggtcaacgc 900cctgttttct
gccctgtaca caaacaagaa cagttgaaac ttttctgtga aacatgtgat 960agattgacat
gtagagactg tcagctattg gaacacaaag aacataggta tcagtttttg 1020gaagaagctt
ttcaaaatca gaagggtgca attgagaatc tactggcgaa acttcttgag 1080aagaagaatt
atgttcattt tgcagctact caggtgcaga ataggataaa agaagtaaat 1140gagactaaca
aacgagtaga acaggaaatt aaagtggcca ttttcaccct tatcaatgaa 1200attaataaga
aaggaaaatc tctcttacaa cagctagaga atgttacaaa ggaaagacag 1260atgaagttac
tacagcagca gaatgacatc acaggccttt cccggcaggt gaagcatgtt 1320atgaacttca
caaattgggc aattgcaagt ggcagcagca cagcactact atacagcaag 1380cgactgatta
ctttccagtt gcgtcatatt ttgaaagcac ggtgtgatcc tgtccctgct 1440gctaatggag
caatacgttt ccattgtgat cccaccttct gggcaaagaa tgtagtcaat 1500ttaggtaatc
tagtaataga gagtaaacca gctcctggtt atactcctaa tgttgtagtt 1560gggcaagttc
ctccagggac aaaccacatt agtaaaaccc ctggacagat taacttagca 1620cagcttcgac
tccagcacat gcaacaacaa gtatatgcac agaaacatca gcagttgcaa 1680cagatgagga
tgcagcaacc accagcacct gtaccaacta caacaacaac aacacaacag 1740catcctagac
aagcagcccc tcagatgtta caacaacagc ctcctcgatt gatcagtgtg 1800caaacaatgc
aaagaggcaa catgaactgt ggagcttttc aagcccatca gatgagactg 1860gctcagaatg
ctgccagaat accagggata cccaggcaca gcggccctca atattccatg 1920atgcagccac
acctccaaag acaacactca aacccagggc atgctggacc ctttcccgta 1980gtatcggtac
acaacaccac aatcaaccca acgagcccta ctacagcaac tatggcaaat 2040gcaaaccgag
gtcccaccag cccatctgtt acagcaatag agctaatccc ctcagttacc 2100aatccagaaa
accttccatc gctgccagat attccaccca tacagttgga agatgctggc 2160tcaagtagtt
tagataatct actaagtaga tacatctcag gcagtcacct acccccacag 2220cctacaagca
ccatgaatcc ttctccaggt ccctctgccc tttctccggg atcatcaggt 2280ttatccaatt
ctcacacacc tgtgagaccc ccaagtactt ctagtactgg cagtcgaggc 2340agctgtgggt
catcaggaag aactgctgag aagacaagtc ttagtttcaa atctgatcag 2400gtgaaggtca
agcaagaacc tgggactgaa gatgaaatat gtagcttttc aggaggtgta 2460aaacaagaaa
aaacagagga tggcaggagg agtgcttgca tgttgagcag tcctgagagt 2520agcttgacac
cacctctctc aaccaacctg catctagaaa gtgaattgga tgcattggca 2580agcctggaaa
accatgtgaa aattgaacct gcagatatga atgaaagctg caaacagtca 2640gggctcagca
gccttgttaa tggaaagtcc ccaattcgaa gcctcatgca caggtcggca 2700aggattggag
gagatggcaa caataaagat gatgacccaa atgaagactg gtgtgctgtc 2760tgccaaaacg
gaggagatct cttgtgctgc gaaaaatgtc caaaggtctt tcatctaact 2820tgtcatgttc
caacactact tagctttcca agtggggact ggatatgcac attttgtaga 2880gatattggaa
agccagaagt tgaatatgat tgtgataatt tgcaacatag taagaagggg 2940aaaactgcgc
aggggttaag ccccgtggac caaaggaaat gtgaacgtct tctgctttac 3000ctctattgcc
atgaattaag tattgaattc caggagcctg ttcctgcttc gataccaaac 3060tactataaaa
ttataaagaa accaatggat ttatccaccg tgaaaaagaa gcttcagaaa 3120aaacattccc
aacactacca aatcccggat gactttgtgg ccgatgtccg tttgatcttc 3180aagaactgtg
aaaggtttaa tgaagctgat tcagaagtag ctcaggcagg gaaagcagtt 3240gcattgtact
ttgaagataa actcacagag atctactcag acaggacctt cgcacctttg 3300ccagagtttg
agcaggaaga ggatgatggt gaggtaactg aggactctga tgaagacttt 3360atacagcccc
gcagaaaacg cctaaagtca gatgagagac cagtacatat aaagtaaaat 3420gacatggatt
taaatcaatt gtttaaaaaa aaaaaaacga aaaaaaaaaa aaaaacacaa 3480aaaacccaga
aaacttttaa gtgttgctgg aatatcctgc ctacagtggg cacctccttg 3540aagaagctga
tagcttttac acagtattag attgaaataa tggacagaaa cacattcttg 3600tcaagaaagg
gggagagaag tctgtttgca agtttcaaag caaaaagcaa aagtgaaatg 3660atttgaggat
ttctgttcta atggagatga ttctctgatt gttagaaatg gcaaatattg 3720atgattgtgt
gctattgatt ggtgcaggat acttggtata cgagtaaata cttgagactc 3780gtgtcacttg
ataaattttc tttttggact aggtcgcaca gttattaaaa caacttttaa 3840ccctccccct
tcacacacat acatatcagg ttgttttcta gttaaaaacc caagtagctc 3900agattctact
ttaatgtcag tgcagatttg cattgaatca tgccattatg ttttttctca 3960tttttatgct
gttgggtctt agtttttaaa ttgatataaa gaactcagca atggttttat 4020tttctactca
tacttagggt ttaggaaaca ctaccactag ttatcattta atcaacttca 4080atggtctact
gaaacaaaaa tggtaacttt tcattagtgg attatttaga gttatagtag 4140ttgtttccag
aaaacacttc ctcacaattg tacttcccaa tcaaatcatg tgatcataca 4200gttattccca
tgaaaggcag aatgtttgtt tcaaaattaa tctagttttc tgtacattta 4260aatttgagaa
ggtgacaact ggctcttttc cagtcttcct tcatgtcagt tttctgatag 4320accactattg
gcaaacagta tctgtcaact accaaatgtg taaaattttc tgtatttcac 4380tttgtcttat
ttgtaaatag tgaactaaaa cttttggcag atcagcaaca tttgctgagc 4440ctgtttttta
agctaatgtg tattcttact aatgttccta tcaagaatgg atttgtaata 4500tatgctgtct
atttctaatg ttcacattca tattttgagg ttctatctta ttttaataga 4560gaacagactt
ctcaaaaaat cttcagaagc agcttattat tgaaatatcg aaatattgaa 4620ataaacccgg
tggggttaga ttactcatct gtccaccaag tgggacattt gcatggactg 4680ggggcttaaa
ggacttagaa gagacctgta agtaaatcct gaaaatgagc caatccccac 4740ttgaatggtt
actggagtaa acccaccttt accaccccaa ttacagcacc cgaggccgat 4800aaaccaactt
ggctctggtt catttttctt ttcttcattt gtgatgctca gattcaaaat 4860gtgtgttcta
cactgttaca ggcttctctt ttgtttgatt aaagatttta gtcctacttt 4920tgtatggaca
cattagaata ttcagagacc aaaatagaag aatttgctgt tagatatttt 4980tcagaagtca
gcagatttgt ggcaaatcat ttatttgcct ttttaaaaat tcatttaagc 5040agttcagaga
gtagactact cagaaaatta tttcacgtaa ttgtctaaga ggtcaatatt 5100ttttaatgca
tattgaatca aataaagtgc tctaaagaaa ttattataca aattcctttg 5160ggttgttttt
cttttcttaa caaggggtgg gggtaaacag gaatatgatt caggctttct 5220ggttgtgtat
ttaaagagta ttgattttat tattactatt gatttacttt attcctggct 5280tccttttcac
ttttctttca atttttaaaa aataatttaa gccgttgaaa atataccaaa 5340ctgttgaaac
attttactca aattttaaat tcctaaaaat gttttttaat aagagggaga 5400aaattattta
aaaatactta tgcctatgcc aatttccctc ttttttcaca aaatccatga 5460tttcagtttg
taagtagaca tatatctaag ggcacatttt tggaaagtga ggaatagcag 5520cagtataact
tcattttgtc aggcctttga gttctaatat tttgtattgc tcttcaaatg 5580gatcctttta
aaaaaattgt agataatgag tcataaatag attctgccaa ctgaggggag 5640aaacatttta
agtaaatatt tttcagtatt tggggcctta aaaaataatt gtgtttcctt 5700aaaattacat
gttagataga gtttttaggt ttttttggtt ttaagattgg ttaaagcaat 5760ttaaaagcca
cttttttgtc aacatttaat agcctccact tctgttaaga taatgtatac 5820tgctgaggaa
ttactattaa tagctatcaa cataccacca ttaaattaag gtattcactt 5880tagatttttt
attaaagctt ttttcttgca cactgatcgt tgtgtttcta agctgatttt 5940ttcagctcta
atatacctat ggttaaaaag tataaaaact taaattgata tttagatata 6000tgttttccta
ttagtttatg ttttaaaaag acaaaattgt atctgtcagt ccctgaaggc 6060agtttgtttt
tatactctct cacatttgta tttgtttttt aaatggcagt attttagaag 6120atttggagaa
aagtccacat aataatgttt tcttaaaagc ttttaaagtt tttgctgtac 6180ttcaatttac
ttcttccatc agaaaactaa gaacaaagtg ttgctcagtc tgttccgctg 6240acctaaattt
gtgttttcag cacttggctc agccaattca ctgagtgaag gaattgcttt 6300atgaggcaaa
gcatgtgaaa gttctaaagt atggttagat tgtaggtcgt gctctatatg 6360gaaacatcaa
accattacta cagagaaatg ataaggcatt ggatccacta ttgaaattat 6420tatttttgga
tcaacaagtt ggtactttct gacttctgta tcttaacata agggaatttt 6480aggtaatgct
aagtcagttg tctcattttt tgtgataagt tttggaattt ttagttaatt 6540gaaataaata
atgcttttaa atagaagtaa aaggtttata agtgtgcaaa ttgtagattt 6600atcaattacc
tcagcaggta tcctgccatg taattattag tgattagtgt taataagata 6660atagattcag
gtcttccaac tatgcccttg gattgtggcc tactgtatgt tattaaatgg 6720tctcttacta
tccaaaatgg gagtagatgc tgtggccccg tctcccttgg cttttacgtc 6780ccatatccac
ccccattcat gtacaacatg tgaaatataa aaatctcatt tcttgtcaaa 6840atcagcactg
cttatttgca tactcagcat cggatcagtg agtagtttta taaaaaatcc 6900acgcacccaa
ctcccttagt taaaacagat tcttaattca taccatgaat tcttaatttc 6960tgtaccatct
atgttaatga tctgctgaag gtgactcaag attttcaagg tgtaatacag 7020tttgatcatg
taccggacct ggatatttaa ttttttttcc ctcacagtta atctcctcct 7080tgataaagca
ataacactgc tttgagtctg ttgcctaata gcatgtcaga atcctctcct 7140ggatggtgat
tttataggaa agtttgtatg catatcaccc agtctatctt ttaaaaatta 7200agaaatttaa
atgtatgctg gaagtaatga cactatattg tggcatttta ttttaaaaat 7260tggggaaagt
tgcatatttt tttaaaagta agtgtttgag taaaaaaatt gaaggtactt 7320ttttaaggaa
aaaaatttat atgccacagt ttacatagac atttcagatt caacacgtac 7380tcttgaatat
aatggtttct tttacttggt caaaatgcat gtatagcatt tctttcatct 7440tagttccttg
tgtttgccta tgtggtcctt tatatatttt ttattgtatc gaagaaacaa 7500aactatcttc
aaaaataagt taatttggat atatttgtca tatcaaacta caaagtgtac 7560aaagttaagt
ttagcccttt tctagaaagt gatctttaaa attaaaaatg ctcctctttt 7620aaattcacca
aatttatgtg tgggaaggca ccaaaatgat tttgtaagtg ccactgcaat 7680attccctttc
aagtgtggcc taaatttcaa tcttaaggat ggaatgcatg tctgctcctt 7740gttctgaaaa
atgtaggcat ctactacatt ttaaaacaca gtgaaacata tacataagcc 7800tataaaaaaa
gatttgtgca atttgaaagc ctgttaattt tttatgtaga catacctaca 7860cacgaaaggg
ttaaattcac agccttacta gttccttgct tccagtattt caattggtct 7920cctcccctca
ttattattat tactactagt actattattt ttgcacatag ttaactgccc 7980ttcaatatga
ttcttaaaaa gtgctgtttc tgtggtatcg tattctctaa ataatcatat 8040ttaatttttt
aaaacaaggt tgcagtttct aattgtttcg ttcctgtgtt tttgctggtg 8100tgtaataaaa
gcaagttttt tcttttcatg gttatttaat acattagctg cctgtaaata 8160attcttgtta
taatgctctg gaatgtgttg tagaagttgt attagattag ttttaaaccc 8220ttgtttgaaa
gccacattgt tttggttatt tctattaaat tagaaaattg aaaaagtttt 8280caaatgaa
8288451127PRTHomo
sapiensmisc_featureTRIM33 isoform alpha (NP_056990.3) 45Met Ala Glu Asn
Lys Gly Gly Gly Glu Ala Glu Ser Gly Gly Gly Gly 1 5
10 15 Ser Gly Ser Ala Pro Val Thr Ala Gly
Ala Ala Gly Pro Ala Ala Gln 20 25
30 Glu Ala Glu Pro Pro Leu Thr Ala Val Leu Val Glu Glu Glu
Glu Glu 35 40 45
Glu Gly Gly Arg Ala Gly Ala Glu Gly Gly Ala Ala Gly Pro Asp Asp 50
55 60 Gly Gly Val Ala Ala
Ala Ser Ser Gly Ser Ala Gln Ala Ala Ser Ser 65 70
75 80 Pro Ala Ala Ser Val Gly Thr Gly Val Ala
Gly Gly Ala Val Ser Thr 85 90
95 Pro Ala Pro Ala Pro Ala Ser Ala Pro Ala Pro Gly Pro Ser Ala
Gly 100 105 110 Pro
Pro Pro Gly Pro Pro Ala Ser Leu Leu Asp Thr Cys Ala Val Cys 115
120 125 Gln Gln Ser Leu Gln Ser
Arg Arg Glu Ala Glu Pro Lys Leu Leu Pro 130 135
140 Cys Leu His Ser Phe Cys Leu Arg Cys Leu
Pro Glu Pro Glu Arg Gln 145 150 155
160 Leu Ser Val Pro Ile Pro Gly Gly Ser Asn Gly Asp Ile Gln Gln
Val 165 170 175 Gly
Val Ile Arg Cys Pro Val Cys Arg Gln Glu Cys Arg Gln Ile Asp
180 185 190 Leu Val Asp Asn Tyr
Phe Val Lys Asp Thr Ser Glu Ala Pro Ser Ser 195
200 205 Ser Asp Glu Lys Ser Glu Gln Val Cys
Thr Ser Cys Glu Asp Asn Ala 210 215
220 Ser Ala Val Gly Phe Cys Val Glu Cys Gly Glu Trp Leu
Cys Lys Thr 225 230 235
240 Cys Ile Glu Ala His Gln Arg Val Lys Phe Thr Lys Asp His Leu Ile
245 250 255 Arg Lys Lys Glu
Asp Val Ser Glu Ser Val Gly Ala Ser Gly Gln Arg 260
265 270 Pro Val Phe Cys Pro Val His Lys Gln
Glu Gln Leu Lys Leu Phe Cys 275 280
285 Glu Thr Cys Asp Arg Leu Thr Cys Arg Asp Cys Gln Leu Leu
Glu His 290 295 300
Lys Glu His Arg Tyr Gln Phe Leu Glu Glu Ala Phe Gln Asn Gln Lys 305
310 315 320 Gly Ala Ile Glu Asn
Leu Leu Ala Lys Leu Leu Glu Lys Lys Asn Tyr 325
330 335 Val His Phe Ala Ala Thr Gln Val Gln Asn
Arg Ile Lys Glu Val Asn 340 345
350 Glu Thr Asn Lys Arg Val Glu Gln Glu Ile Lys Val Ala Ile Phe
Thr 355 360 365 Leu
Ile Asn Glu Ile Asn Lys Lys Gly Lys Ser Leu Leu Gln Gln Leu 370
375 380 Glu Asn Val Thr Lys
Glu Arg Gln Met Lys Leu Leu Gln Gln Gln Asn 385 390
395 400 Asp Ile Thr Gly Leu Ser Arg Gln Val Lys
His Val Met Asn Phe Thr 405 410
415 Asn Trp Ala Ile Ala Ser Gly Ser Ser Thr Ala Leu Leu Tyr Ser
Lys 420 425 430 Arg
Leu Ile Thr Phe Gln Leu Arg His Ile Leu Lys Ala Arg Cys Asp 435
440 445 Pro Val Pro Ala Ala Asn
Gly Ala Ile Arg Phe His Cys Asp Pro Thr 450 455
460 Phe Trp Ala Lys Asn Val Val Asn Leu Gly
Asn Leu Val Ile Glu Ser 465 470 475
480 Lys Pro Ala Pro Gly Tyr Thr Pro Asn Val Val Val Gly Gln Val
Pro 485 490 495 Pro
Gly Thr Asn His Ile Ser Lys Thr Pro Gly Gln Ile Asn Leu Ala
500 505 510 Gln Leu Arg Leu Gln
His Met Gln Gln Gln Val Tyr Ala Gln Lys His 515
520 525 Gln Gln Leu Gln Gln Met Arg Met Gln
Gln Pro Pro Ala Pro Val Pro 530 535
540 Thr Thr Thr Thr Thr Thr Gln Gln His Pro Arg Gln Ala
Ala Pro Gln 545 550 555
560 Met Leu Gln Gln Gln Pro Pro Arg Leu Ile Ser Val Gln Thr Met Gln
565 570 575 Arg Gly Asn Met
Asn Cys Gly Ala Phe Gln Ala His Gln Met Arg Leu 580
585 590 Ala Gln Asn Ala Ala Arg Ile Pro Gly
Ile Pro Arg His Ser Gly Pro 595 600
605 Gln Tyr Ser Met Met Gln Pro His Leu Gln Arg Gln His Ser
Asn Pro 610 615 620
Gly His Ala Gly Pro Phe Pro Val Val Ser Val His Asn Thr Thr Ile 625
630 635 640 Asn Pro Thr Ser Pro
Thr Thr Ala Thr Met Ala Asn Ala Asn Arg Gly 645
650 655 Pro Thr Ser Pro Ser Val Thr Ala Ile Glu
Leu Ile Pro Ser Val Thr 660 665
670 Asn Pro Glu Asn Leu Pro Ser Leu Pro Asp Ile Pro Pro Ile Gln
Leu 675 680 685 Glu
Asp Ala Gly Ser Ser Ser Leu Asp Asn Leu Leu Ser Arg Tyr Ile 690
695 700 Ser Gly Ser His Leu
Pro Pro Gln Pro Thr Ser Thr Met Asn Pro Ser 705 710
715 720 Pro Gly Pro Ser Ala Leu Ser Pro Gly Ser
Ser Gly Leu Ser Asn Ser 725 730
735 His Thr Pro Val Arg Pro Pro Ser Thr Ser Ser Thr Gly Ser Arg
Gly 740 745 750 Ser
Cys Gly Ser Ser Gly Arg Thr Ala Glu Lys Thr Ser Leu Ser Phe 755
760 765 Lys Ser Asp Gln Val Lys
Val Lys Gln Glu Pro Gly Thr Glu Asp Glu 770 775
780 Ile Cys Ser Phe Ser Gly Gly Val Lys Gln
Glu Lys Thr Glu Asp Gly 785 790 795
800 Arg Arg Ser Ala Cys Met Leu Ser Ser Pro Glu Ser Ser Leu Thr
Pro 805 810 815 Pro
Leu Ser Thr Asn Leu His Leu Glu Ser Glu Leu Asp Ala Leu Ala
820 825 830 Ser Leu Glu Asn His
Val Lys Ile Glu Pro Ala Asp Met Asn Glu Ser 835
840 845 Cys Lys Gln Ser Gly Leu Ser Ser Leu
Val Asn Gly Lys Ser Pro Ile 850 855
860 Arg Ser Leu Met His Arg Ser Ala Arg Ile Gly Gly Asp
Gly Asn Asn 865 870 875
880 Lys Asp Asp Asp Pro Asn Glu Asp Trp Cys Ala Val Cys Gln Asn Gly
885 890 895 Gly Asp Leu Leu
Cys Cys Glu Lys Cys Pro Lys Val Phe His Leu Thr 900
905 910 Cys His Val Pro Thr Leu Leu Ser Phe
Pro Ser Gly Asp Trp Ile Cys 915 920
925 Thr Phe Cys Arg Asp Ile Gly Lys Pro Glu Val Glu Tyr Asp
Cys Asp 930 935 940
Asn Leu Gln His Ser Lys Lys Gly Lys Thr Ala Gln Gly Leu Ser Pro 945
950 955 960 Val Asp Gln Arg Lys
Cys Glu Arg Leu Leu Leu Tyr Leu Tyr Cys His 965
970 975 Glu Leu Ser Ile Glu Phe Gln Glu Pro Val
Pro Ala Ser Ile Pro Asn 980 985
990 Tyr Tyr Lys Ile Ile Lys Lys Pro Met Asp Leu Ser Thr Val
Lys Lys 995 1000 1005
Lys Leu Gln Lys Lys His Ser Gln His Tyr Gln Ile Pro Asp Asp 1010
1015 1020 Phe Val Ala Asp Val
Arg Leu Ile Phe Lys Asn Cys Glu Arg Phe 1025 1030
1035 Asn Glu Met Met Lys Val Val Gln Val Tyr
Ala Asp Thr Gln Glu 1040 1045 1050
Ile Asn Leu Lys Ala Asp Ser Glu Val Ala Gln Ala Gly Lys Ala
1055 1060 1065 Val Ala
Leu Tyr Phe Glu Asp Lys Leu Thr Glu Ile Tyr Ser Asp 1070
1075 1080 Arg Thr Phe Ala Pro Leu Pro
Glu Phe Glu Gln Glu Glu Asp Asp 1085 1090
1095 Gly Glu Val Thr Glu Asp Ser Asp Glu Asp Phe Ile
Gln Pro Arg 1100 1105 1110
Arg Lys Arg Leu Lys Ser Asp Glu Arg Pro Val His Ile Lys 1115
1120 1125 461110PRTHomo
sapiensmisc_featureTRIM33 isoform beta (NP_148980.2) 46Met Ala Glu Asn
Lys Gly Gly Gly Glu Ala Glu Ser Gly Gly Gly Gly 1 5
10 15 Ser Gly Ser Ala Pro Val Thr Ala Gly
Ala Ala Gly Pro Ala Ala Gln 20 25
30 Glu Ala Glu Pro Pro Leu Thr Ala Val Leu Val Glu Glu Glu
Glu Glu 35 40 45
Glu Gly Gly Arg Ala Gly Ala Glu Gly Gly Ala Ala Gly Pro Asp Asp 50
55 60 Gly Gly Val Ala Ala
Ala Ser Ser Gly Ser Ala Gln Ala Ala Ser Ser 65 70
75 80 Pro Ala Ala Ser Val Gly Thr Gly Val Ala
Gly Gly Ala Val Ser Thr 85 90
95 Pro Ala Pro Ala Pro Ala Ser Ala Pro Ala Pro Gly Pro Ser Ala
Gly 100 105 110 Pro
Pro Pro Gly Pro Pro Ala Ser Leu Leu Asp Thr Cys Ala Val Cys 115
120 125 Gln Gln Ser Leu Gln Ser
Arg Arg Glu Ala Glu Pro Lys Leu Leu Pro 130 135
140 Cys Leu His Ser Phe Cys Leu Arg Cys Leu Pro
Glu Pro Glu Arg Gln 145 150 155
160 Leu Ser Val Pro Ile Pro Gly Gly Ser Asn Gly Asp Ile Gln Gln Val
165 170 175 Gly Val
Ile Arg Cys Pro Val Cys Arg Gln Glu Cys Arg Gln Ile Asp 180
185 190 Leu Val Asp Asn Tyr Phe Val
Lys Asp Thr Ser Glu Ala Pro Ser Ser 195 200
205 Ser Asp Glu Lys Ser Glu Gln Val Cys Thr Ser Cys
Glu Asp Asn Ala 210 215 220
Ser Ala Val Gly Phe Cys Val Glu Cys Gly Glu Trp Leu Cys Lys Thr 225
230 235 240 Cys Ile Glu
Ala His Gln Arg Val Lys Phe Thr Lys Asp His Leu Ile 245
250 255 Arg Lys Lys Glu Asp Val Ser Glu
Ser Val Gly Ala Ser Gly Gln Arg 260 265
270 Pro Val Phe Cys Pro Val His Lys Gln Glu Gln Leu Lys
Leu Phe Cys 275 280 285
Glu Thr Cys Asp Arg Leu Thr Cys Arg Asp Cys Gln Leu Leu Glu His 290
295 300 Lys Glu His Arg
Tyr Gln Phe Leu Glu Glu Ala Phe Gln Asn Gln Lys 305 310
315 320 Gly Ala Ile Glu Asn Leu Leu Ala Lys
Leu Leu Glu Lys Lys Asn Tyr 325 330
335 Val His Phe Ala Ala Thr Gln Val Gln Asn Arg Ile Lys Glu
Val Asn 340 345 350
Glu Thr Asn Lys Arg Val Glu Gln Glu Ile Lys Val Ala Ile Phe Thr
355 360 365 Leu Ile Asn Glu
Ile Asn Lys Lys Gly Lys Ser Leu Leu Gln Gln Leu 370
375 380 Glu Asn Val Thr Lys Glu Arg Gln
Met Lys Leu Leu Gln Gln Gln Asn 385 390
395 400 Asp Ile Thr Gly Leu Ser Arg Gln Val Lys His Val
Met Asn Phe Thr 405 410
415 Asn Trp Ala Ile Ala Ser Gly Ser Ser Thr Ala Leu Leu Tyr Ser Lys
420 425 430 Arg Leu Ile
Thr Phe Gln Leu Arg His Ile Leu Lys Ala Arg Cys Asp 435
440 445 Pro Val Pro Ala Ala Asn Gly Ala
Ile Arg Phe His Cys Asp Pro Thr 450 455
460 Phe Trp Ala Lys Asn Val Val Asn Leu Gly Asn Leu Val
Ile Glu Ser 465 470 475
480 Lys Pro Ala Pro Gly Tyr Thr Pro Asn Val Val Val Gly Gln Val Pro
485 490 495 Pro Gly Thr Asn
His Ile Ser Lys Thr Pro Gly Gln Ile Asn Leu Ala 500
505 510 Gln Leu Arg Leu Gln His Met Gln Gln
Gln Val Tyr Ala Gln Lys His 515 520
525 Gln Gln Leu Gln Gln Met Arg Met Gln Gln Pro Pro Ala Pro
Val Pro 530 535 540
Thr Thr Thr Thr Thr Thr Gln Gln His Pro Arg Gln Ala Ala Pro Gln 545
550 555 560 Met Leu Gln Gln Gln
Pro Pro Arg Leu Ile Ser Val Gln Thr Met Gln 565
570 575 Arg Gly Asn Met Asn Cys Gly Ala Phe Gln
Ala His Gln Met Arg Leu 580 585
590 Ala Gln Asn Ala Ala Arg Ile Pro Gly Ile Pro Arg His Ser Gly
Pro 595 600 605 Gln
Tyr Ser Met Met Gln Pro His Leu Gln Arg Gln His Ser Asn Pro 610
615 620 Gly His Ala Gly Pro Phe
Pro Val Val Ser Val His Asn Thr Thr Ile 625 630
635 640 Asn Pro Thr Ser Pro Thr Thr Ala Thr Met Ala
Asn Ala Asn Arg Gly 645 650
655 Pro Thr Ser Pro Ser Val Thr Ala Ile Glu Leu Ile Pro Ser Val Thr
660 665 670 Asn Pro
Glu Asn Leu Pro Ser Leu Pro Asp Ile Pro Pro Ile Gln Leu 675
680 685 Glu Asp Ala Gly Ser Ser Ser
Leu Asp Asn Leu Leu Ser Arg Tyr Ile 690 695
700 Ser Gly Ser His Leu Pro Pro Gln Pro Thr Ser Thr
Met Asn Pro Ser 705 710 715
720 Pro Gly Pro Ser Ala Leu Ser Pro Gly Ser Ser Gly Leu Ser Asn Ser
725 730 735 His Thr Pro
Val Arg Pro Pro Ser Thr Ser Ser Thr Gly Ser Arg Gly 740
745 750 Ser Cys Gly Ser Ser Gly Arg Thr
Ala Glu Lys Thr Ser Leu Ser Phe 755 760
765 Lys Ser Asp Gln Val Lys Val Lys Gln Glu Pro Gly Thr
Glu Asp Glu 770 775 780
Ile Cys Ser Phe Ser Gly Gly Val Lys Gln Glu Lys Thr Glu Asp Gly 785
790 795 800 Arg Arg Ser Ala
Cys Met Leu Ser Ser Pro Glu Ser Ser Leu Thr Pro 805
810 815 Pro Leu Ser Thr Asn Leu His Leu Glu
Ser Glu Leu Asp Ala Leu Ala 820 825
830 Ser Leu Glu Asn His Val Lys Ile Glu Pro Ala Asp Met Asn
Glu Ser 835 840 845
Cys Lys Gln Ser Gly Leu Ser Ser Leu Val Asn Gly Lys Ser Pro Ile 850
855 860 Arg Ser Leu Met His
Arg Ser Ala Arg Ile Gly Gly Asp Gly Asn Asn 865 870
875 880 Lys Asp Asp Asp Pro Asn Glu Asp Trp Cys
Ala Val Cys Gln Asn Gly 885 890
895 Gly Asp Leu Leu Cys Cys Glu Lys Cys Pro Lys Val Phe His Leu
Thr 900 905 910 Cys
His Val Pro Thr Leu Leu Ser Phe Pro Ser Gly Asp Trp Ile Cys 915
920 925 Thr Phe Cys Arg Asp Ile
Gly Lys Pro Glu Val Glu Tyr Asp Cys Asp 930 935
940 Asn Leu Gln His Ser Lys Lys Gly Lys Thr Ala
Gln Gly Leu Ser Pro 945 950 955
960 Val Asp Gln Arg Lys Cys Glu Arg Leu Leu Leu Tyr Leu Tyr Cys His
965 970 975 Glu Leu
Ser Ile Glu Phe Gln Glu Pro Val Pro Ala Ser Ile Pro Asn 980
985 990 Tyr Tyr Lys Ile Ile Lys Lys
Pro Met Asp Leu Ser Thr Val Lys Lys 995 1000
1005 Lys Leu Gln Lys Lys His Ser Gln His Tyr
Gln Ile Pro Asp Asp 1010 1015 1020
Phe Val Ala Asp Val Arg Leu Ile Phe Lys Asn Cys Glu Arg Phe
1025 1030 1035 Asn Glu
Ala Asp Ser Glu Val Ala Gln Ala Gly Lys Ala Val Ala 1040
1045 1050 Leu Tyr Phe Glu Asp Lys Leu
Thr Glu Ile Tyr Ser Asp Arg Thr 1055 1060
1065 Phe Ala Pro Leu Pro Glu Phe Glu Gln Glu Glu Asp
Asp Gly Glu 1070 1075 1080
Val Thr Glu Asp Ser Asp Glu Asp Phe Ile Gln Pro Arg Arg Lys 1085
1090 1095 Arg Leu Lys Ser Asp
Glu Arg Pro Val His Ile Lys 1100 1105
1110
User Contributions:
Comment about this patent or add new information about this topic: